Ip receptor agonist heterocyclic compounds

ABSTRACT

The present invention provides heterocyclic derivatives which activate the IP receptor, processes for preparing them, pharmaceutical compositions comprising said derivatives and uses thereof. Activating the IP receptor signaling pathway is useful to treat many forms of PAH, pulmonary fibrosis and exert beneficial effects in fibrotic conditions of various organs in animal models and in patients.

CROSS-REFERENCE TO RELATED APPLICATION

This application is the U.S. National Stage patent application, whichclaims the benefit of priority to U.S. Provisional Application Ser. No.61/586,546, filed on Jan. 13, 2012, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Prostacyclin (or PGI2) is a member of the family of lipid moleculesknown as eicosanoids. It is a potent vasodilator, antiproliferative,anti-thrombotic agent that mediates its effects as an agonist of the IPreceptor. The IP receptor is a G-protein coupled receptor that, uponactivation by prostacyclin, stimulates the formation of cyclic adenosinemonophosphate (cAMP). Prostacyclin counteracts the vasoconstrictor andpro-thrombotic activity of endothelin.

Pulmonary arterial hypertension (PAH) is a life-threatening diseasecharacterized by a progressive pulmonary vasculopathy leading to rightventricular hypertrophy. Exogenous administration of an agonist of theIP receptor has become an important strategy in the treatment of PAH.(See, e.g., Tuder et al., Am. J. Respir. Crit. Care. Med., 1999, 159:1925-1932; Humbert et al, J. Am. Coll. Cardiol., 2004, 43:13 S-24S;Rosenzweig, Expert Opin. Emerging Drugs, 2006, 11:609-619; McLaughlin etal, Circulation, 2006, 114:1417-1431; Rosenkranz, Clin. Res. Cardiol.,2007, 96:527-541; Driscoll et al, Expert Opin. Pharmacother., 2008,9:65-81.).

The prostacyclin analogue epoprostenol (flolan) is at least as effectiveas transplantation in terms of survival. Despite this, it is not used asfrontline therapy due to significant tolerability, convenience and costissues. Instead, patients with PAH are often treated first with eitherendothelin receptor antagonists (e.g. bosentan) and/or PDE5 inhibitors(e.g. sildenafil), which are better tolerated but can have limitedefficacy. Prostacyclin analogues are used mainly as add-on treatment asseverity of the disease progresses and tolerability and conveniencebecome less of an issue.

Two key issues prevent current prostacyclin analogues being used asfrontline therapy in PAH. Firstly, they are very unstable with anextremely short half-life, meaning they must be constantly infused viaan in-dwelling intra venous (i.v.) catheter that is both inconvenientfor the patient and also associated with a significant risk of infectionand sepsis. Secondly, they are associated with significant side effectsincluding nausea, jaw pain, headache and other side effects associatedwith systemic hypotension.

One solution to these issues is iloprost, which is available as anebulised formulation that has reduced tolerability issues, but theshort half life results in a 6-9 times daily dosing regime. Morerecently, researchers made efforts to generate stable, orally availableIP receptor agonists. These ligands would improve patient convenienceand compliance, but high levels of systemic drug is required to achievepharmacodynamic effects in the lung; thus, possibly generating similarside effects to those observed with i.v. flolan.

The present invention describes stable, highly selective IP receptoragonists that are suitable for oral and inhaled delivery. The presentinvention offers a significant improvement over existing prostacyclinanalogues and enables their use in less-severe patients. In addition,long term activation of the IP receptor has been shown to reverseremodeling associated with PAH; therefore, earlier intervention with thepresent invention may have significant effects on disease progressionand potentially may show reversal.

In addition, pharmaceutical research has considerable interest indeveloping IP receptor agonists for the treatment of pulmonary fibrosis.IP deficient mice have been shown to be more susceptible tobleomycin-induced lung fibrosis than wild-type animals (Lovgren A K etal. (2006) Am J Physiol Lung Cell Mol. Physiol. 291:L144-56), and the IPreceptor agonist iloprost increases survival in bleomycin-treated mice(Zhu et al (2010) Respir Res. 11(1):34).

Furthermore, IP receptor signaling has been shown to exert beneficialeffects in fibrotic conditions of various organs in animal models and inpatients. Benefits of IP receptor agonist were shown for fibrosis of theheart, lung, skin, pancreas and liver, and in systemic sclerosis.(Gayraud M (2007) Joint Bone Spine. 74(1):e1-8; Hirata Y et al (2009)Biomed Pharmacother. 63(10):781-6; Kaneshige T et al (2007) J Vet Med.Sci. 69(12):1271-6; Sahsivar M O et al (2009) Shock 32(5):498-502; SatoN et al (2010) Diabetes 59(4):1092-100; Shouval D S et al (2008) ClinExp Rheumatol. 26(3 Suppl 49):5105-7; Spargias K et al (2009)Circulation. 120(18):1793-9; Stratton R et al (2001) J Clin Invest.108(2):241-50; Takenaka M et al (2009) Prostaglandins Leukot EssentFatty Acids. 80(5-6):263-7; Watanabe M et al (2009) Am J. Nephrol.30(1):1-11; Yano T et al (2005) Am J Pathol. 166(5):1333-42; Zardi E Met al (2007) Expert Opin Biol Ther. 7(6):785-90; Zardi E M et al (2006)In Vivo 20(3):377-80; Rehberger P et al (2009) Acta Derm Venereol.89(3):245-9). Fibrotic conditions can occur in most organs secondary tochronic inflammation indications throughout the body and are likely toshare common causes. Therefore, antifibrotic agents such as IP receptoragonists of the present invention are of potential benefit in allindications that are associated with fibrotic tissue remodeling.

There is considerable interest in developing agonists of the IP receptorfor use in the treatment of other diseases, such as atherothrombosis,preeclampsia. It is highly desirable to develop stable, inhaled agonistsof the IP receptor, which may lead to improved management of PAH.

The invention pertains to the compounds, methods for using them, anduses thereof as described herein. Examples of compounds of the inventioninclude the compounds according to any of Formula I, or apharmaceutically acceptable salt thereof, and the compounds of theexamples.

In a first aspect, there is provided a compound represented by formula

or a pharmaceutically acceptable salt thereof, wherein

A is N or CR;

R′ is H, C₁-C₈ alkyl optionally substituted by one or more halogenatoms;R¹ is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; —(C₂-C₄ alkyl)-NR¹⁹R²¹ and C₃-C₇ cycloalkyl; or

R¹ is —X—Y; or R¹ is —W—R⁷—X—Y; or R¹ is —S(O)₂—X—Y; or R¹ is—S(O)₂—W—R⁷—X—Y;

R² is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; C₁-C₄ alkoxy; —(C₀-C₄ alkyl)-NR¹⁹R²¹ and C₃-C₇cycloalkyl; or

R² is —X—Y; or R² is —W—R⁷—X—Y; or R² is —S(O)₂—X—Y; or R² is—S(O)₂—W—R⁷—X—Y;

R^(2a) is selected from H; C₁-C₈ alkyl optionally substituted by one ormore halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; and C₃-C₇ cycloalkyl; orR² and R^(2a) taken together are oxo;wherein one of R¹ and R² is —X—Y, —W—R⁷—X—Y, —S(O)₂—X—Y; or—S(O)₂—W—R⁷—X—Y;R³ is independently selected from H; C₁-C₈ alkyl optionally substitutedby one or more halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl orC₃-C₇ cycloalkyloxy; —OH; OR′; —(C₀-C₄alkyl)-NR¹⁹R²¹; CN; halogen;—(C₀-C₄alkyl)-C₆-C₁₄aryl; —(C₀-C₄alkyl)-4 to 14 membered heteroaryl;—C(═O)H; —C(═O)OH; —C(═O)NR¹⁹R²¹ and C₃-C₇ cycloalkyl, wherein the aryland heteroaryl are optionally substituted by one or more substituentsindependently selected from OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogens andC₁-C₄ haloalkyl;R^(3a) is selected from H; C₁-C₈ alkyl optionally substituted by one ormore halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; and C₃-C₇ cycloalkyl; orR³ and R^(3a) taken together are oxo;

R⁵ and R⁶ are independently selected from —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and—(C₀-C₄ alkyl)-4 to 14 membered heteroaryl, wherein the aryl andheteroaryl are each optionally substituted by one or more Zsubstituents;

W is C₁-C₈ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;X is C₁-C₈ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;Y is carboxy, C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or—CONH—S(O)_(q)—R^(x), whereinR^(x) is phenyl, benzyl or —NR¹⁹R²¹;q is 0, 1 or 2;R⁷ is a divalent moiety represented by —O—, —S—, —NHC(O)—, —CH₂═CH₂—,—C₆-C₁₄ aryl-D-; -3 to 14 membered heterocyclyl-D-, wherein theheterocyclyl contains at least one heteroatom selected from N, O and S,wherein D is O, S, NH or not present;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups, C₁-C₆ alkoxy optionallysubstituted by one or more halogen, C₁-C₆ alkoxy optionally substitutedby C₁-C₄ alkoxy, NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹, (SO₂)R²¹, C(O)NR¹⁹R²¹,NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹,oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclyl, wherein theheterocyclyl contains at least one heteroatom selected from N, O and S;R¹⁸ is independently H or C₁-C₆ alkyl;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; —(C₁-C₄ alkyl)-carboxy; (C₀-C₄ alkyl)-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; (C₀-C₄ alkyl)-3- to 14-membered heterocyclyl,the heterocyclyl including one or more heteroatoms selected from N, Oand S, optionally substituted by one or more groups selected fromhalogen, oxo, C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-memberedheterocyclyl, the heterocyclyl including one or more heteroatomsselected from N, O and S, optionally substituted by one or more groupsselected from halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl;wherein the alkyl groups are optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C(O)NH₂, C(O)NHC₁-C₆ alkyl orC(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclyl, the heterocyclyl including one or morefurther heteroatoms selected from N, O and S, the heterocyclyl beingoptionally substituted by one or more substituents selected from OH;halogen; aryl; 5- to 10-membered heterocyclyl including one or moreheteroatoms selected from N, O and S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl;C₁-C₆ alkyl optionally substituted by one or more halogen atoms; C₁-C₆alkoxy optionally substituted by one or more OH groups or C₁-C₄ alkoxy;and C(O)OC₁-C₆ alkyl, wherein the aryl and heterocyclyl substituentgroups are themselves optionally substituted by C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ alkoxy.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

DEFINITIONS

Terms used in the specification have the following meanings:

“Optionally substituted” means the group referred to can be substitutedat one or more positions by any one or any combination of the radicalslisted thereafter.

“Optionally substituted by one or more Z groups” denotes that therelevant group may include one or more substituents, each independentlyselected from the groups included within the definition of Z. Thus,where there are two or more Z group substituents, these may be the sameor different.

“Halo” or “halogen”, as used herein, may be fluorine, chlorine, bromineor iodine.

“C₁-C₈-Alkyl”, as used herein, denotes straight chain or branched alkylhaving 1-8 carbon atoms. If a different number of carbon atoms isspecified, such as C₆ or C₃, then the definition is to be amendedaccordingly, such as “C₁-C₄-Alkyl” will represent methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

“C₁-C₈-Alkoxy”, as used herein, denotes straight chain or branchedalkoxy having 1-8 carbon atoms. If a different number of carbon atoms isspecified, such as C₆ or C₃, then the definition is to be amendedaccordingly, such as “C₁-C₄-Alkoxy” will represent methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

“C₁-C₄-Haloalkyl”, as used herein, denotes straight chain or branchedalkyl having 1-4 carbon atoms with at least one hydrogen substitutedwith a halogen. If a different number of carbon atoms is specified, suchas C₆ or C₃, then the definition is to be amended accordingly, such as“C₁-C₄-Haloalkyl” will represent methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl that have at least onehydrogen substituted with halogen, such as where the halogen isfluorine: CF₃CF₂—, (CF₃)₂CH—, CH₃—CF₂—, CF₃CF₂—, CF₃, CF₂H—, CF₃CF₂CHCF₃or CF₃CF₂CF₂CF₂—.

The term “alkylene” is a straight or branched alkylene (divalent alkylchain) having 1 to 8 carbon atoms, for example, methylene, ethylene,1-methylethylene, 2-methylethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, heptamethylene, and octamethylene.

“C₃-C₁₅ Cycloalkyl”, as used herein, denotes a carbocyclic group having3- to 15-ring carbon atoms that is saturated or partially saturated,such as a C₃-C₈-cycloalkyl. Examples of C₃-C₁₅-carbocyclic groupsinclude but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl or a bicyclic group, such asbicyclooctyl, bicyclononyl including indanyl and indenyl andbicyclodecyl. If a different number of carbon atoms is specified, suchas C₆, then the definition is to be amended accordingly.

“aryl” or “C₆-C₁₅-Aromatic carbocyclic group”, as used herein, denotesan aromatic group having 6- to 15-ring carbon atoms. Examples ofC₆-C₁₅-aromatic carbocyclic groups include, but are not limited to,phenyl, phenylene, benzenetriyl, naphthyl, naphthylene, naphthalenetriylor anthrylene. If a different number of carbon atoms is specified, suchas C_(m), then the definition is to be amended accordingly.

“4- to 8-Membered heterocyclyl”, “5- to 6-membered heterocyclyl”, “3- to10-membered heterocyclyl”, “3- to 14-membered heterocyclyl”, “4- to14-membered heterocyclyl” and “5- to 14-membered heterocyclyl”, refers,respectively, to 4- to 8-membered, 5- to 6-membered, 3- to 10-membered,3- to 14-membered, 4- to 14-membered and 5- to 14-membered heterocyclicrings containing at least one ring heteroatom selected from the groupconsisting of nitrogen, oxygen and sulphur, which may be saturated,partially saturated or unsaturated (aromatic). The heterocyclyl includessingle ring groups, fused ring groups and bridged groups. Examples ofsuch heterocyclyl include, but are not limited to, furan, pyrrole,pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole,thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine,oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine,pyrrolidine, pyrrolidinone, morpholine, triazine, oxazine,tetrahyrofuran, tetrahydrothiophene, tetrahydrothiopyran,tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, indazole, quinoline,indazole, indole, 8-aza-bicyclo[3.2.1]octane, 2,3-dihydrobenzofuran orthiazole.

“Heteroaryl” is a subset of heterocyclyl, wherein the completelyunsaturated (aromatic). Examples of such groups are pyridine andpyrazine.

The term “hydroxy” or “hydroxyl” includes groups with an —OH.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus. In one embodiment, “heteroatom” includes nitrogen, sulfurand oxygen.

The term “carboxy” refers to carboxylic acid.

The term “alkoxycarboxy” refers to an ester.

The term “carbamoyl” is —C(O)NH₂. The terms “monoalkylcarbamoyl” and“dialkylcarbamoyl” are carbamoyl, wherein the hydrogen or hydrogens onthe nitrogen are substituted with C₁-C₈ alkyl as described above.

In an embodiment (i) of the first aspect,

wherein one of R¹ and R² is —X—Y, —W—R⁷—X—Y, —S(O)₂—X—Y; or—S(O)₂—W—R⁷—X—Y;

W is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

X is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

Y is carboxy, C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or—CONH—S(O)_(q)—R^(x),

wherein R^(x) is phenyl, benzyl or —NR¹⁹R²¹;

q is 2;

R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O; and

R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl.

In an embodiment (ii) of the first aspect,

wherein one of R¹ and R² is —X—Y or —W—R⁷—X—Y;

W is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

X is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

Y is carboxy, C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or—CONH—S(O)_(q)—R^(x), wherein R^(x) is phenyl, benzyl or —NR¹⁹R²¹;

q is 2;

R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O; and

R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl.

In an embodiment (iii) of the first aspect,

one of R¹ and R² is —X—Y or —W—R⁷—X—Y;

W is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

X is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

Y is —C(O)OH; and

R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O.

In an embodiment (iv) of the first aspect,

one of R¹ and R² is —(CH₂)_(m)—C(O)OR″, or—(CH₂)_(m)—R⁷—(CH₂)_(n)—C(O)OR″;

m is 1, 2, 3, 4, 5, 6, 7 or 8;

n is 0, 1, 2 or 3;

R″ is H or C₁-C₄ alkyl optionally substituted by one or more halogenatoms; and

R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O.

In an embodiment (v) of the first aspect,

one of R¹ and R² is —(CH₂)_(m)—C(O)OR″;

m is 3, 4, 5, 6, 7 or 8; and

R″ is H or C₁-C₄ alkyl optionally substituted by one or more halogenatoms.

In an embodiment (vi) of the first aspect,

one of R¹ and R² is —(CH₂)_(m)—C(O)OR″;

R″ is H; and

m is 4, 5 or 6.

In an embodiment (vii) of the first aspect,

one of R¹ and R² is

In an embodiment (viii) of the first aspect,

R² is H, C₁-C₈ alkyl optionally substituted by one or more halogenatoms, C₁-C₄ alkoxy, C₃-C₇cycloalkyl, OH, or OR′;

R^(2a) is H; or

R² and R^(2a) together are oxo;

R′ is H, C₁-C₄ alkyl.

In an embodiment (ix) of the first aspect,

R² is H, C₁-C₈ alkyl optionally substituted by one or more halogenatoms, C₁-C₄ alkoxy, C₃-C₇cycloalkyl, OH, or OR′.

In an embodiment (x) of the first aspect,

R² is H, C₁-C₄ alkyl optionally substituted by one or more halogenatoms, or C₃-C₇cycloalkyl.

In an embodiment (xi) of the first aspect,

R² is H.

In an embodiment (xii) of the first aspect,

R³ and R^(3a) are independently selected from H; C₁-C₄ alkyl optionallysubstituted by one or more halogen atoms or OH; —C(═O)H and OH; or R³and R^(3a) taken together are oxo.

In an embodiment (xiii) of the first aspect,

R⁵ and R⁶ are independently selected from C₆-C₁₄ aryl and 5 to 6membered heteroaryl, wherein the heteroaryl contains at least oneheteroatom selected from N, O and S, wherein the aryl and heteroaryl areeach optionally substituted by one or more Z substituents.

In an embodiment (xiv) of the first aspect,

R⁵ and R⁶ are independently selected from phenyl; 2-pyridyl, 3-pyridyl,or 4-pyridyl,

wherein the phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl are eachoptionally substituted by one or more Z substituents.

In an embodiment (xv) of the first aspect,

R⁵ and R⁶ are independently selected from phenyl optionally substitutedby OH, C₁-C₄ alkyl optionally substituted by one or more OH groups orNH₂ groups; C₁-C₄ alkyl optionally substituted by one or more halogenatoms; C₁-C₄ alkoxy optionally substituted by one or more OH groups orC₁-C₄ alkoxy; NR¹⁹R²¹; C(O)OR¹⁹; C(O)R¹⁹; SR¹⁹; OR¹⁹; CN; NO₂; andhalogen.

In an embodiment (xvi) of the first aspect,

R⁵ and R⁶ are independently selected from phenyl optionally substitutedby C₁-C₄ alkyl optionally substituted by one or more OH groups or NH₂groups; C₁-C₄ alkyl optionally substituted by one or more halogen atoms;C₁-C₄ alkoxy optionally substituted by one or more OH groups or C₁-C₄alkoxy; and halogen.

In an embodiment (xvii) of the first aspect,

R⁵ and R⁶ are independently selected from phenyl optionally substitutedby C₁-C₄ alkoxy or halogen, and C₁-C₄ alkyl optionally substituted byone or more halogen atoms.

In an embodiment (xviii) of the first aspect,

R⁵ and R⁶ are independently selected from phenyl optionally substitutedby methyl, ethyl, trifluoromethyl, methoxy or halogen.

In an embodiment (ixx) of the first aspect,

R⁵ is

and

R⁶ is

In an embodiment (xx) of the first aspect, A is N.

In an embodiment (xxi) of the first aspect, A is CR′.

In an embodiment (xxii) of the first aspect, R′ is H.

In an embodiment (xxiii) of the first aspect, formula Ib has thefollowing stereochemistry:

In an embodiment (xxiv) of the first aspect, the compound is selectedfrom

-   7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid; ethyl    7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(6-isopropyl-2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid; ethyl    7-(6-isopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl    ester;-   7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid;-   7-(7-formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   ethyl    7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   ethyl    7-(7-((isopropylamino)methyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(7-((isopropylamino)methyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-methoxy-2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid;-   ethyl    7-(2,3-di-p-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   5-(2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)-pentanoic acid;-   2-(5-(2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)acetic    acid;-   7-(6-methyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid;-   7-(6-cyclopropyl-2-(4-methoxy-phenyl)-3-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(2,3-bis(4-chlorophenyl)-6-cyclopropyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2-(4-ethylphenyl)-3-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2,3-di-m-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(4-ethylphenyl)-2-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(4-methoxyphenyl)-2-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(m-tolyl)-2-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2-(m-tolyl)-3-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-(2-Hydroxyethyl)-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   5-(6-Cyclopropyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)pentanoic    acid;-   6-(6-Cyclopropyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)hexanoic    acid;-   7-(7-(Methoxymethyl)-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-oxo-2,3-dip-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(2,3-Dip-tolyl-6-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid; and-   7-(6,7-Diethyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;    or a pharmaceutically acceptable salt thereof.

In a second aspect, the invention provides a compound as defined in thefirst aspect, or a pharmaceutically acceptable salt thereof, as definedanywhere herein for use as a medicament.

Activating the IP receptor has been shown to have a beneficial effect ortreat the following diseases or disorders: PAH is selected from:idiopathic PAH; familial PAH; PAH associated with a collagen vasculardisease selected from: scleroderma, CREST syndrome, systemic lupuserythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,polymyositis, and dermatomyositis; PAH associated with a congenitalheart disease selected from: atrial septic defect (ASD), ventricularseptic defect (VSD) and patent ductus arteriosus in an individual; PAHassociated with portal hypertension; PAH associated with HIV infection;PAH associated with ingestion of a drug or toxin; PAH associated withhereditary hemorrhagic telangiectasia; PAH associated with splenectomy;PAH associated with significant venous or capillary involvement; PAHassociated with pulmonary veno-occlusive disease (PVOD); and PAHassociated with pulmonary capillary hemangiomatosis (PCH); Raynaud'sphenomenon, including Raynaud's disease and Raynaud's syndrome; fibroticdiseases, including pulmonary fibrosis, systemic sclerosis/scleroderma,hepatic fibrosis/cirrhosis, renal fibrosis; thrombotic diseasesassociated with excessive platelet aggregation, coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke,ischemia-reperfusion injury, restenosis, atrial fibrillation, blood clotformation, atherosclerosis, atherothrombosis, asthma, a symptom ofasthma, a diabetic-related disorder, diabetic peripheral neuropathy,diabetic nephropathy, diabetic retinopathy, glaucoma or other disease ofthe eye with abnormal intraocular pressure, hypertension, preeclampsia,inflammation, prophylaxis against unwanted side effects of COX-1, COX-2and non-selective COX inhibitors, psoriasis, psoriatic arthritis,rheumatoid arthritis, Crohn's disease, transplant rejection, multiplesclerosis, systemic lupus erythematosus (SLE), ulcerative colitis,ischemia-reperfusion injury, restenosis, atherosclerosis, acne, type 1diabetes, type 2 diabetes, sepsis and chronic obstructive pulmonarydisorder (COPD).

Hence, in a third aspect of the invention, there is provided a compoundas defined in the first aspect, or a pharmaceutically acceptable saltthereof, for use in the treatment of a disorder selected from theaforementioned diseases and disorders.

In an embodiment of the third aspect of the invention, there is provideda compound as defined in the first aspect, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of PAH as describedabove.

In a fourth aspect of the present invention, there is provided the useof a compound as defined in the first aspect and in any of theaforementioned embodiments, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the treatment ofpulmonary arterial hypertension.

An embodiment of the fourth aspect of the present invention provides forthe use of a compound as defined in the first aspect and in any of theaforementioned embodiments, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the treatment of PAHselected from: idiopathic PAH; familial PAH; PAH associated with acollagen vascular disease selected from: scleroderma, CREST syndrome,systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu'sarteritis, polymyositis, and dermatomyositis; PAH associated with acongenital heart disease selected from: atrial septic defect (ASD),ventricular septic defect (VSD) and patent ductus arteriosus in anindividual; PAH associated with portal hypertension; PAH associated withHIV infection; PAH associated with ingestion of a drug or toxin; PAHassociated with hereditary hemorrhagic telangiectasia; PAH associatedwith splenectomy; PAH associated with significant venous or capillaryinvolvement; PAH associated with pulmonary veno-occlusive disease(PVOD); and PAH associated with pulmonary capillary hemangiomatosis(PCH).

In a fifth aspect, the present invention provides a method for theprevention or treatment of an IP receptor mediated condition or disease,particularly PAH, comprising administering an effective amount of atleast one compound as described herein to a subject in need of suchtreatment. Such IP receptor mediated conditions or diseases are selectedfrom: idiopathic PAH; familial PAH; PAH associated with a collagenvascular disease selected from: scleroderma, CREST syndrome, systemiclupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis,polymyositis, and dermatomyositis; PAH associated with a congenitalheart disease selected from: atrial septic defect (ASD), ventricularseptic defect (VSD) and patent ductus arteriosus in an individual; PAHassociated with portal hypertension; PAH associated with HIV infection;PAH associated with ingestion of a drug or toxin; PAH associated withhereditary hemorrhagic telangiectasia; PAH associated with splenectomy;PAH associated with significant venous or capillary involvement; PAHassociated with pulmonary veno-occlusive disease (PVOD); and PAHassociated with pulmonary capillary hemangiomatosis (PCH).

Other IP receptor mediated conditions or diseases are selected fromplatelet aggregation, coronary artery disease, myocardial infarction,transient ischemic attack, angina, stroke, ischemia-reperfusion injury,restenosis, atrial fibrillation, blood clot formation, atherosclerosis,atherothrombosis, asthma, a symptom of asthma, a diabetic-relateddisorder, diabetic peripheral neuropathy, diabetic nephropathy, diabeticretinopathy, glaucoma or other disease of the eye with abnormalintraocular pressure, hypertension, inflammation, psoriasis, psoriaticarthritis, rheumatoid arthritis, Crohn's disease, transplant rejection,multiple sclerosis, systemic lupus erythematosus (SLE), ulcerativecolitis, ischemia-reperfusion injury, restenosis, atherosclerosis, acne,type 1 diabetes, type 2 diabetes, sepsis and chronic obstructivepulmonary disorder (COPD).

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations such as“comprises” or “comprising”, should be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which typically are not biologically orotherwise undesirable. In many cases, the compounds as defined in thefirst aspect are capable of forming acid and/or base salts by virtue ofthe presence of amino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylatetrifluoroacetate and xinafoate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, 1-hydroxy-2-naphtoic acid and sulfosalicylic acid.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, acetone or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Furthermore, the compounds as defined in the first aspect, includingtheir salts, can also be obtained in the form of their hydrates, orinclude other solvents used for their crystallization.

Compounds as defined in the first aspect that contain groups capable ofacting as donors and/or acceptors for hydrogen bonds may be capable offorming co-crystals with suitable co-crystal formers. These co-crystalsmay be prepared from compounds as defined in the first aspect by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsas defined in the first aspect with the co-crystal former undercrystallization conditions and isolating co-crystals thereby formed.Suitable co-crystal formers include those described in WO 2004/078163.Hence the invention further provides co-crystals comprising a compoundof as defined in the first aspect.

As used herein, the term “an optical isomer” or “a stereoisomer” refersto any of the various stereo isomeric configurations which may exist fora given compound of the present invention and includes geometricisomers. It is understood that a substituent may be attached at a chiralcenter of a carbon atom. Therefore, the invention includes enantiomers,diastereomers or racemates of the compound. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term isused to designate a racemic mixture where appropriate.“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. Certain ofthe compounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, including racemic mixtures, opticallypure forms and intermediate mixtures. Optically active (R)- and(S)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques. If the compound contains adouble bond, the substituent may be E or Z configuration. If thecompound contains a disubstituted cycloalkyl, the cycloalkyl substituentmay have a cis- or trans-configuration. All tautomeric forms are alsointended to be included.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds as defined in the first aspect intotheir optical antipodes, e.g., by fractional crystallization of a saltformed with an optically active acid, e.g., tartaric acid, dibenzoyltartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid,mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic productscan also be resolved by chiral chromatography, e.g., high pressureliquid chromatography (HPLC) using a chiral adsorbent.

Since the compounds as defined in the first aspect are intended for usein pharmaceutical compositions it will readily be understood that theyare each preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of theinvention.

Compounds as defined in the first aspect are either obtained in the freeform, as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds as defined in the first aspect may also forminternal salts, e.g., zwitterionic molecules.

The present invention also provides pro-drugs of the compounds asdefined in the first aspect that converts in vivo to the compounds asdefined in the first aspect. A pro-drug is an active or inactivecompound that is modified chemically through in vivo physiologicalaction, such as hydrolysis, metabolism and the like, into a compound ofthis invention following administration of the prodrug to a subject. Thesuitability and techniques involved in making and using pro-drugs arewell known by those skilled in the art. Prodrugs can be conceptuallydivided into two non-exclusive categories, bioprecursor prodrugs andcarrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32(Ed. Wermuth, Academic Press, San Diego, Calif., 2001). Generally,bioprecursor prodrugs are compounds, which are inactive or have lowactivity compared to the corresponding active drug compound that containone or more protective groups and are converted to an active form bymetabolism or solvolysis. Both the active drug form and any releasedmetabolic products should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof (a) hydroxyl groups with lipophilic carboxylic acids (e.g., acarboxylic acid having at least one lipophilic moiety), or (b)carboxylic acid groups with lipophilic alcohols (e.g., an alcohol havingat least one lipophilic moiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acylderivatives of thiols and O-acyl derivatives of alcohols or phenols,wherein acyl has a meaning as defined herein. Suitable prodrugs areoften pharmaceutically acceptable ester derivatives convertible bysolvolysis under physiological conditions to the parent carboxylic acid,e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters,benzyl esters, mono- or di-substituted lower alkyl esters, such as thew-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart. In addition, amines have been masked as arylcarbonyloxymethylsubstituted derivatives which are cleaved by esterases in vivo releasingthe free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).Moreover, drugs containing an acidic NH group, such as imidazole, imide,indole and the like, have been masked with N-acyloxymethyl groups(Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups havebeen masked as esters and ethers. EP 039,051 (Sloan and Little)discloses Mannich-base hydroxamic acid prodrugs, their preparation anduse.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds as defined in the first aspect includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S,³⁶Cl, ¹²⁵I respectively. The invention includes various isotopicallylabeled compounds as defined herein, for example those into whichradioactive isotopes, such as ³H, ¹³C, and ¹⁴C, are present. Suchisotopically labeled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the schemes or in the examplesand preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound as defined in the first aspect. Theconcentration of such a heavier isotope, specifically deuterium, may bedefined by the isotopic enrichment factor. The term “isotopic enrichmentfactor” as used herein means the ratio between the isotopic abundanceand the natural abundance of a specified isotope. If a substituent in acompound of this invention is denoted deuterium, such compound has anisotopic enrichment factor for each designated deuterium atom of atleast 3500 (52.5% deuterium incorporation at each designated deuteriumatom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5%deuterium incorporation), at least 5000 (75% deuterium incorporation),at least 5500 (82.5% deuterium incorporation), at least 6000 (90%deuterium incorporation), at least 6333.3 (95% deuterium incorporation),at least 6466.7 (97% deuterium incorporation), at least 6600 (99%deuterium incorporation), or at least 6633.3 (99.5% deuteriumincorporation).

Isotopically-labeled compounds as defined in the first aspect cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Synthesis

Generally, compounds according to Formula I, or a pharmaceuticallyacceptable salt thereof, can be synthesized by the routes described inSchemes 1-5 and the Examples.

Scheme 1 begins with a Step 1 bromination. Step 2 is a Sonogashiracoupling. Step 3 is a cyclisation. Step 4 is an alkylation. Steps 5 and6 are subsequent Suzuki reactions. Step 7 is an ester hydrolysis ifrequired. A, R¹, R², R⁵ and R⁶ are as defined in embodiment 1 of theconsistory clauses.

Scheme 2 begins with a Step 1 iodination. Step 2 is a Suzuki coupling.Step 3 is a bromination. Step 4 is a Sonogashira coupling. Step 5 is acyclisation. Step 6 is an alkylation. Step 7 is an ester hydrolysis ifrequired. A, R¹, R², R⁵ and R⁶ are as defined in embodiment 1 of theconsistory clauses.

Scheme 3 begins with a Step 1 iodination. Step 2 is a Suzuki coupling.Step 3 is a bromination. Step 4 is a Sonogashira coupling. Step 5 is acyclisation. Step 6 is an alkylation. Step 7 is either a Vilsmeyerformylation followed by reductive amination; or oxidation and thencoupling; or reduction followed by an alkylation if required; orbromination followed by an alkylation, or suzuki coupling or Grignard,Step 8 is an ester hydrolysis if required. A, R¹, R², R³, R⁵ and R⁶ areas defined in embodiment 1 of the consistory clauses.

Scheme 4 begins with a Step 1 iodination. Step 2 is a Suzuki coupling.Step 3 is a bromination. Step 4 is a Sonogashira coupling. Step 5 is acyclisation. Step 6 is an alkylation. Step 7 is a hydrogenation, Step 8is an ester hydrolysis if required.

Scheme 5 begins with a Step 1 iodination. Step 2 is a Suzuki coupling.Step 3 is a bromination. Step 4 is a Sonogashira coupling. Step 5 is acyclisation. Step 6 is an alkylation. Step 7 is an ester hydrolysis ifrequired. Step 8 is a bromination (NBS) followed by a hydrogenation.

The skilled person will appreciate that the general synthetic routesdetailed above show common reactions to transform the starting materialsas required. The specific reaction conditions are not provided, butthese are well known to those skilled in the art and appropriateconditions considered to be within the skilled person's common generalknowledge.

The starting materials are either commercially available compounds orare known compounds and can be prepared from procedures described in theorganic chemistry art.

Compounds as defined in the first aspect, in free form, may be convertedinto salt form, and vice versa, in a conventional manner understood bythose skilled in the art. The compounds in free or salt form can beobtained in the form of hydrates or solvates containing a solvent usedfor crystallisation. Compounds as defined in the first aspect can berecovered from reaction mixtures and purified in a conventional manner.Isomers, such as stereoisomers, may be obtained in a conventionalmanner, e.g., by fractional crystallisation or asymmetric synthesis fromcorrespondingly asymmetrically substituted, e.g., optically active,starting materials.

Compounds as defined in the first aspect or a pharmaceuticallyacceptable salt thereof can be prepared, e.g., using the reactions andtechniques described below and in the Examples. The reactions may beperformed in a solvent appropriate to the reagents and materialsemployed and suitable for the transformations being effected. It will beunderstood by those skilled in the art of organic synthesis that thefunctionality present on the molecule should be consistent with thetransformations proposed. This will sometimes require a judgment tomodify the order of the synthetic steps or to select one particularprocess scheme over another in order to obtain a desired compound of theinvention.

The various substituents on the synthetic intermediates and finalproducts shown in the following reaction schemes can be present in theirfully elaborated forms, with suitable protecting groups where requiredas understood by one skilled in the art, or in precursor forms which canlater be elaborated into their final forms by methods familiar to oneskilled in the art. The substituents can also be added at various stagesthroughout the synthetic sequence or after completion of the syntheticsequence. In many cases, commonly used functional group manipulationscan be used to transform one intermediate into another intermediate, orone compound as defined in the first aspect into another compound asdefined in the first aspect. Examples of such manipulations areconversion of an ester or a ketone to an alcohol; conversion of an esterto a ketone; interconversions of esters, acids and amides; alkylation,acylation and sulfonylation of alcohols and amines; and many others.Substituents can also be added using common reactions, such asalkylation, acylation, halogenation or oxidation. Such manipulations arewell-known in the art, and many reference works summarize procedures andmethods for such manipulations. Some reference works which givesexamples and references to the primary literature of organic synthesisfor many functional group manipulations, as well as othertransformations commonly used in the art of organic synthesis areMarch's Organic Chemistry, 5^(th) Edition, Wiley and Chichester, Eds.(2001); Comprehensive Organic Transformations, Larock, Ed., VCH (1989);Comprehensive Organic Functional Group Transformations, Katritzky et al.(series editors), Pergamon (1995); and Comprehensive Organic Synthesis,Trost and Fleming (series editors), Pergamon (1991). It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. Multiple protecting groupswithin the same molecule can be chosen such that each of theseprotecting groups can either be removed without removal of otherprotecting groups in the same molecule, or several protecting groups canbe removed using the same reaction step, depending upon the outcomedesired. An authoritative account describing many alternatives to thetrained practitioner is Greene and Wuts, Protective Groups in OrganicSynthesis,Wiley and Sons, 4^(th) Edition (2006).

Pharmacological Activity

The compounds disclosed herein activate the IP receptor and are usefulin the treatment of several diseases and disorders, and in theamelioration of symptoms thereof.

Without limitation, these include the following:

Pulmonary Arterial Hypertension (PAH)

PAH has a multifactorial pathobiology. Vasoconstriction, remodeling ofthe pulmonary vessel wall, and thrombosis contribute to increasedpulmonary vascular resistance in PAH (Humbert et al, J. Am. Coll.Cardiol., 2004, 43:13 S-24S.). The compounds as defined in the firstaspect disclosed herein are useful in the treatment of pulmonaryarterial hypertension (PAH) and symptoms thereof. PAH shall beunderstood to encompass the following forms of pulmonary arterialhypertension described in the 2003 World Health Organization (WHO)clinical classification of pulmonary arterial hypertension: idiopathicPAH (BPAH); familial PAH (FPAH); PAH associated with other conditions(APAH), such as PAH associated with collagen vascular disease, PAHassociated with congenital systemic-to-pulmonary shunts, PAH associatedwith portal hypertension, PAH associated with HTV infection, PAHassociated with drugs or toxins, or PAH associated with Other; and PAHassociated with significant venous or capillary involvement. IdiopathicPAH refers to PAH of undetermined cause. Familial PAH refers to PAH forwhich hereditary transmission is suspected or documented. PAH associatedwith collagen vascular disease shall be understood to encompass PAHassociated with scleroderma, PAH associated with CREST (calcinosiscutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyl), andtelangiectasias) syndrome, PAH associated with systemic lupuserythematosus (SLE), PAH associated with rheumatoid arthritis, PAHassociated with Takayasu's arteritis, PAH associated with polymyositis,and PAH associated with dermatomyositis. PAH associated with congenitalsysterruc-to-pulmonary shunts shall be understood to encompass PAHassociated with atrial septic defect (ASD), PAH associated withventricular septic defect (VSD) and PAH associated with patent ductusarteriosus.

PAH associated with drugs or toxins shall be understood to encompass PAHassociated with ingestion of a minorex, PAH associated with ingestion ofa fenfluramine compound (e.g., PAH associated with ingestion offenfluramine or PAH associated with ingestion of dexfenfluramine), PAHassociated with ingestion of certain toxic oils (eg, PAH associated withingestion of rapeseed oil), PAH associated with ingestion ofpyrrolizidine alkaloids (e.g, PAH associated with ingestion of bush tea)and PAH associated with ingestion of monocrotaline. PAH associated withOther shall be understood to encompass PAH associated with a thyroiddisorder, PAH associated with glycogen storage disease, PAH associatedwith Gaucher disease, PAH associated with hereditary hemorrhagictelangiectasia, PAH associated with a hemoglobinopathy, PAH associatedwith a myeloproliferative disorder, and PAH associated with splenectomy.PAH associated with significant venous or capillary involvement shall beunderstood to encompass PAH associated with pulmonary veno-occlusivedisease (PVOD) and PAH associated with pulmonary capillaryhemangiomatosis (PCH). (See, e.g, Simonneau et al, J. Am. Coll.Cardiol., 2004, 43:5 S-12S; McGoon et al., Chest, 2004, 126:14 S-34S;Rabinovitch, Annu Rev. Pathol. Mech. Dis., 2007, 2:369-399; McLaughlinet al, Circulation, 2006, 114:1417-1431; Strauss et al, Clin. Chest.Med., 2007, 28:127-142; Taichman et al., Clin. Chest. Med., 2007,28:1-22.).

Evidence for the association of PAH with scleroderma and the beneficialeffect of an agonist of the IP receptor on PAH is given by Badesch et al(Badesch et al, Ann. Intern. Med., 2000, 132:425-434). Evidence for theassociation of PAH with the collagen vascular diseases mixed connectivetissue disease (MCTD), systemic lupus erythematosus (SLE), Sjogren'ssyndrome and CREST syndrome and the beneficial effect of an agonist ofthe IP receptor on PAH is given by Humbert et al. (Eur. Respir. J.,1999, 13:1351-1356). Evidence for the association of PAH with CRESTsyndrome and the beneficial effect of an agonist of the IP receptor onPAH is given by Miwa et al. (Int. Heart J., 2007, 48:417-422). Evidencefor the association of PAH with SLE and the beneficial effect of anagonist of the IP receptor on PAH is given by Robbins et al (Chest,2000, 117:14-18). Evidence for the association of PAH with HIV infectionand the beneficial of an agonist of the IP receptor on PAH is given byAguilar et al. (Am. J. Respir. Crit. Care Med., 2000, 162:1846-1850).Evidence for the association of PAH with congenital heart defects(including ASD, VSD and patent ductus arteriosus) and the beneficialeffect of an agonist of the IP receptor on PAH is given by Rosenzweig etal. (Circulation, 1999, 99:1858-1865).

Evidence for the association of PAH with fenfluramine and withdexfenfluramine, anorexigens, is given by Archer et al. (Am. J. Respir.Crit. Care Med., 1998, 158: 1061-1067). Evidence for the association ofPAH with hereditary hemorrhagic telangiectasia is given by McGoon et al.(Chest, 2004, 126:14-34). Evidence for the association of PAH withsplenectomy is given by Hoeper et al. (Ann. Intern. Med., 1999,130:506-509). Evidence for the association of PAH with portalhypertension and the beneficial effect of an agonist of the IP receptoron PAH is given by Hoeper et al. (Eur. Respir. J., 2005, 25:502-508).

Symptoms of PAH include dyspnea, angina, syncope and edema (McLaughlinet al., Circulation, 2006, 114:1417-1431). The compounds as defined inthe first aspect disclosed herein are useful in the treatment ofsymptoms of PAH.

Antiplatelet Therapies (Conditions Related to Platelet Aggregation)

Antiplatelet agents (antiplatelets) are prescribed for a variety ofconditions. For example, in coronary artery disease they are used tohelp prevent myocardial infarction or stroke in patients who are at riskof developing obstructive blood clots (e.g., coronary thrombosis).

In a myocardial infarction, the heart muscle does not receive enoughoxygen-rich blood as a result of a blockage in the coronary bloodvessels. If taken while an attack is in progress or immediatelyafterward (preferably within 30 min), antiplatelets can reduce thedamage to the heart.

A transient ischemic attack (“TIA” or “mini-stroke”) is a briefinterruption of oxygen flow to the brain due to decreased blood flowthrough arteries, usually due to an obstructing blood clot. Antiplateletdrugs have been found to be effective in preventing TIAs. Angina is atemporary and often recurring chest pain, pressure or discomfort causedby inadequate oxygen-rich blood flow (ischemia) to some parts of theheart. In patients with angina, antiplatelet therapy can reduce theeffects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enoughoxygen-rich blood, usually due to blockage of a cerebral blood vessel bya blood clot. In high-risk patients, taking antiplatelets regularly hasbeen found to prevent the formation of blood clots that cause first orsecond strokes. Angioplasty is a catheter based technique used to openarteries obstructed by a blood clot. Whether or not stenting isperformed immediately after this procedure to keep the artery open,antiplatelets can reduce the risk of forming additional blood clotsfollowing the procedure(s).

Coronary bypass surgery is a surgical procedure in which an artery orvein is taken from elsewhere in the body and grafted to a blockedcoronary artery, rerouting blood around the blockage and through thenewly attached vessel. After the procedure, antiplatelets can reduce therisk of secondary blood clots.

Atrial fibrillation is the most common type of sustained irregular heartrhythm (arrhythmia). Atrial fibrillation affects about two millionAmericans every year. In atrial fibrillation, the atria (the heart'supper chambers) rapidly fire electrical signals that cause them toquiver rather than contract normally. The result is an abnormally fastand highly irregular heartbeat. When given after an episode of atrialfibrillation, antiplatelets can reduce the risk of blood clots formingin the heart and traveling to the brain (embolism).

There is evidence that an IP receptor agonist will inhibit plateletaggregation and thus be a potential treatment as an antiplatelet therapy(see, e.g., Moncada et al., Lancet, 1977, 1: 18-20). It has been shownthat genetic deficiency of the IP receptor in mice leads to an increasedpropensity towards thrombosis (Murata et al, Nature, 1997, 388:678-682).

IP receptor agonists can be used to treat, for example, claudication orperipheral artery disease as well as cardiovascular complications,arterial thrombosis, atherosclerosis, vasoconstriction caused byserotonin, ischemia-reperfusion injury, and restenosis of arteriesfollowing angioplasty or stent placement. (See, e.g., Fetalvero et al,Prostaglandins Other Lipid Mediat., 2007, 82:109-118; Arehart et al,Curr. Med. Chem., 2007, 14:2161-2169; Davi et al, N. Engl. J. Med.,2007, 357:2482-2494; Fetalvero et al, Am. J. Physiol. Heart. Circ.Physiol., 2006, 290:H1337-H1346; Murata et al, Nature, 1997,388:678-682; Wang et al, Proc. Natl. Acad. Sci. USA, 2006,103:14507-14512; Xiao et al, Circulation, 2001, 104:2210-2215; McCormicket al, Biochem. Soc. Trans., 2007, 35:910-911; Arehart et al, Circ.Res., 2008, Mar. 6.).

IP receptor agonists can also be used alone or in combination withthrombolytic therapy, for example, tissue-type plasminogen activator(t-PA), to provide cardioprotection following MI or postischemicmyocardial dysfunction or protection from ischemic injury duringpercutaneous coronary intervention, and the like, includingcomplications resulting therefrom. IP receptor agonists can also be usedin antiplatelet therapies in combination with, for example,alpha-tocopherol (vitamin E), echistatin (a disintegrin) or, in statesof hypercoagulability, heparin. (See, e.g., Chan., J. Nutr., 1998,128:1593-1596; Mardla et al, Platelets, 2004, 15:319-324; Bernabei etal, Ann. Thorac. Surg., 1995, 59:149-153; Gainza et al, J. Nephrol.,2006, 19:648-655.)

The IP receptor agonists disclosed herein may provide beneficialimprovement in microcirculation to patients in need of antiplatelettherapy by antagonizing the vasoconstrictive products of the aggregatingplatelets in, for example and not limited to the indications describedabove.

Accordingly, in some embodiments, the present invention provides methodsfor reducing platelet aggregation in a patient in need thereof,comprising administering to the patient a composition comprising an IPreceptor agonist disclosed herein. In further embodiments, the presentinvention provides methods for treating coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing in a patient in needof the treatment, comprising administering to the patient a compositioncomprising an IP receptor agonist disclosed herein.

In further embodiments, the present invention provides methods forreducing risk of blood clot formation in an angioplasty or coronarybypass surgery patient, or a patient suffering from atrial fibrillation,comprising administering to the patient a composition comprising an IPreceptor agonist disclosed herein at a time where such risk exists.

Atherosclerosis

Atherosclerosis is a complex disease characterized by inflammation,lipid accumulation, cell death and fibrosis. It is the leading cause ofmortality in many countries, including the United States.Atherosclerosis, as the term is used herein, shall be understood toencompass disorders of large and medium-sized arteries that result inthe progressive accumulation within the intima of smooth muscle cellsand lipids.

It has been shown that an agonist of the IP receptor can conferprotection from atherosclerosis, such as from atherothrombosis (Arehartet al, Curr. Med. Chem., 2007, 14:2161-2169; Stitham et al,Prostaglandins Other Lipid Mediat., 2007, 82:95-108; Fries et al,Hematology Am. Soc. Hematol. Educ. Program, 2005:445-451; Egan et al,Science, 2004, 306:1954-1957; Kobayashi et al, J. Clin. Invest, 2004,114:784-794; Arehart et al, Circ. Res., 2008, Mar. 6). It has been shownthat defective IP receptor signaling appears to accelerateatherothrombosis in humans, i e that an agonist of the IP receptor canconfer protection from atherothrombosis in humans (Arehart et al, Circ.Res., 2008, Mar. 6.)

The compounds as defined in the first aspect disclosed herein are usefulin the treatment of atherosclerosis, and the treatment of the symptomsthereof. Accordingly, in some embodiments, the present inventionprovides methods for treating atherosclerosis in a patient in need ofthe treatment, comprising administering to the patient a compositioncomprising an IP receptor agonist disclosed herein. In furtherembodiments, methods are provided for treating a symptom ofatherosclerosis in a patient in need of the treatment, comprisingadministering to the patient a composition comprising an IP receptoragonist disclosed herein.

Asthma

Asthma is a lymphocyte-mediated inflammatory airway disordercharacterised by airway eosinophilia, increased mucus production bygoblet cells, and structural remodeling of the airway wall. Theprevalence of asthma has dramatically increased worldwide in recentdecades. It has been shown that genetic deficiency of the IP receptor inmice augments allergic airway inflammation (Takahashi et al, Br JPharmacol, 2002, 137:315-322). It has been shown that an agonist of theIP receptor can suppress not only the development of asthma when givenduring the sensitization phase, but also the cardinal features ofexperimental asthma when given during the challenge phase (Idzko et al,J. Clin. Invest., 2007, 117:464-72, Nagao et al, Am. J. Respir. CellMoI. Biol., 2003, 29:314-320), at least in part through markedlyinterfering with the function of antigen-presenting dendnuc cells withinthe airways (Idzko et al., J. Clin. Invest., 2007, 117:464-472; Zhou etal, J. Immunol., 2007, 178:702-710; Jaffar et al., J. Immunol., 2007,179:6193-6203; Jozefowski et al, Int. Immunopharmacol., 2003,3:865-878). These cells are crucial for both the initiation and themaintenance phases of allergic asthma, as depletion of airway dendriticcells during secondary challenge in sensitized mice abolished allcharacteristic features of asthma, an effect that could be completelyrestored by adoptive transfer of wild-type dendritic cells (van Rijt etal., J. Exp. Med., 2005, 201:981-991). It has also been shown that anagonist of the IP receptor can inhibit proinflammatory cytokinesecretion by human alveolar macrophages (Raychaudhuri et al., J. Biol.Chem., 2002, 277:33344-33348). The compounds as defined in the firstaspect disclosed herein are useful in the treatment of asthma, and thetreatment of the symptoms thereof. Accordingly, in some embodiments, thepresent invention provides methods for treating asthma in a patient inneed of the treatment, comprising administering to the patient acomposition comprising IP receptor agonist disclosed herein.

In further embodiments, methods are provided for treating a symptom ofasthma in a patient in need of the treatment, comprising administeringto the patient a composition comprising IP receptor agonist disclosedherein.

Chronic Obstructive Pulmonary Disease

Activation of the IP-receptor may also be beneficial in chronicobstructive pulmonary disease (COPD). Taprostene, an IP-receptoragonist, suppressed the generation of the CD8⁺ T cell chemoattractantsCXCL9 and CXCL10 from human airway epithelial cells in vitro. (Ayer, L.M., S. M. Wilson, S. L. Traves, D. Proud, M. A. Giembycz. 2008. J.Pharmacol. Exp. Ther. 324: 815-826.) Beraprost, an IP-receptor agonist,protected rats against the development of experimental cigarettesmoke-induced emphysema, possibly by means of a concerted inhibitoryaction on alveolar epithelial cell apoptosis, oxidative burden, matrixmetalloproteinase expression, and proinflammatory cytokine generation.(Chen, Y, M Hanaoka, P. Chen, Y. Droma, N. F. Voelkel, K. Kubo. 2009.Am. J. Physiol. 296: L648-L656.)

In further embodiments, methods are provided for treating COPD in apatient in need of the treatment, comprising administering to thepatient a composition comprising IP receptor agonist disclosed herein.

Hyperglycemia

Although hyperglycemia is the major cause for the pathogenesis ofdiabetic complications such as diabetic peripheral neuropathy (DPN),diabetic nephropathy (DN) and diabetic retinopathy (DR), enhancedvasoconstriction and platelet aggregation in diabetic patients has alsobeen implicated to play a role in disease progression (Cameron et al.,Naunyn Schmiedebergs Arch. Pharmacol., 2003, 367:607-614). Agonists ofthe IP receptor promote vasodilation and inhibit platelet aggregation.Improving microvascular blood flow is able to benefit diabeticcomplications (Cameron, Diabetologia, 2001, 44:1973-1988).

It has been shown that an agonist of the IP receptor can prevent andreverse motor and sensory peripheral nerve conduction abnormalities instreptozotocin-diabetic rats (Cotter et al., Naunyn Schmiedebergs Arch.Pharmacol., 1993, 347:534-540). Further evidence for the beneficialeffect of an agonist of the IP receptor in the treatment of diabeticperipheral neuropathy is given by Hotta et al. (Diabetes, 1996,45:361-366), Ueno et al. (Jpn. J. Pharmacol., 1996, 70:177-182), Ueno etal. (Life Sci., 1996, 59:PL105-PL110), Hotta et al. (Prostaglandins,1995, 49:339-349), Shindo et al. (Prostaglandins, 1991, 41:85-96), Okudaet al. (Prostaglandins, 1996, 52:375-384), and Koike et al. (FASEB J.,2003, 17:779-781).

Evidence for the beneficial effect of an agonist of the IP receptor inthe treatment of diabetic nephropathy is given by Owada et al. (Nephron,2002, 92:788-796) and Yamashita et al. (Diabetes Res. Clin. Pract.,2002, 57:149-161). Evidence for the beneficial effect of an agonist ofthe IP receptor in the treatment of diabetic retinopathy is given byYamagishi et al. (MoI. Med., 2002, 8:546-550), Burnette et al. (Exp. EyeRes., 2006, 83: 1359-1365), and Hotta et al. (Diabetes, 1996,45:361-366). It has been shown that an agonist of the IP receptor canreduce increased tumor necrosis factor-[alpha] (TNF-[alpha]) levels indiabetic patients, implying that an agonist of the IP receptor maycontribute to the prevention of progression in diabetic complications(Fujiwara et al, Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394).

Evidence that topical administration of an agonist of the IP receptorcan result in a decrease in intraocular pressure (IOP) in rabbits anddogs and thereby have beneficial effect in the treatment of glaucoma isgiven by Hoyng et al (Hoyng et al, Invest. Ophthalmol. Vis. Sci., 1987,28:470-476).

Agonists of the IP receptor have been shown to have activity forregulation of vascular tone, for vasodilation, and for amelioration ofpulmonary hypertension (see, e.g., Strauss et al, Clin Chest Med, 2007,28:127-142; Driscoll et al, Expert Opin. Pharmacother., 2008, 9:65-81).Evidence for a beneficial effect of an agonist of the IP receptor in thetreatment of hypertension is given by Yamada et al. (Peptides, 2008,29:412-418). Evidence that an agonist of the IP receptor can protectagainst cerebral ischemia is given by Dogan et al. (Gen. Pharmacol.,1996, 27:1163-1166) and Fang et al (J. Cereb. Blood Flow Metab., 2006,26:491-501).

Anti-Inflammation

Anti-inflammation agents are prescribed for a variety of conditions. Forexample, in an inflammatory disease they are used to interfere with andthereby reduce an underlying deleterious.

There is evidence that an IP receptor agonist can inhibit inflammationand thus be a potential treatment as an anti-inflammation therapy. Ithas been shown that an agonist of the IP receptor can inhibitpro-inflammatory cytokine and chemokine (interleukin-12 (IL-12), tumornecrosis factor-[alpha] (TNF-[alpha]), DL-1[alpha], EL-6, macrophageinflammatory protein-1 alpha (MIP-1[alpha]), monocyte chemoattractantprotein-1 (MCP-I)) production and T cell stimulatory function ofdendritic cells (Jozefowski et al, Int. Immunopharmacol., 2003, 865-878;Zhou et al, J. Immunol., 2007, 178:702-710; Nagao et al, Am. J. Respir.Cell MoI. Biol., 2003, 29:314-320; Idzko et al, J. Clin. Invest., 2007,117:464-472). It has been shown that an agonist of the IP receptor caninhibit pro-inflammatory cytokine (TNF-[alpha], IL-1/3, EL-6,granulocyte macrophage stimulating factor (GM-CSF)) production bymacrophages (Raychaudhuri et al, J. Biol. Chem., 2002, 277:33344-33348;Czeslick et al, Eur. J. Clin. Invest., 2003, 33:1013-1017; Di Renzo etal, Prostaglandin Leukot. Essent. Fatty Acids, 2005, 73:405-410;Shinomiya et al, Biochem. Pharmacol., 2001, 61:1153-1160). It has beenshown that an agonist of the IP receptor can stimulate anti-inflammatorycytokine (DL-IO) production by dendritic cells (Jozefowski et al, Int.Immunopharmacol., 2003, 865-878; Zhou et al, J. Immunol., 2007,178:702-710). It has been shown that an agonist of the IP receptor canstimulate anti-inflammatory cytokine (DL-10) production by macrophages(Shinomiya et al, Biochem. Pharmacol., 2001, 61: 1153-1160). It has beenshown that an agonist of the IP receptor can inhibit a chemokine (CCL17)-induced chemotaxis of leukocytes (CD4<+>Th2 T cells) (Jaffar et al,J. Immunol., 2007, 179:6193-6203). It has been shown that an agonist ofthe IP receptor can confer protection from atherosclerosis, such as fromatherothrombosis (Arehart et al, Curr. Med. Chem., 2007, 14:2161-2169;Stitham et al, Prostaglandins Other Lipid Mediat., 2007, 82:95-108;Fries et al, Hematology Am. Soc. Hematol. Educ. Program, 2005:445-451;Egan et al, Science, 2004, 306:1954-1957; Kobayashi et al, J. Clin.Invest., 2004, 114:784-794; Arehart et al, Circ. Res., 2008, Mar. 6). Ithas been shown that an agonist of the IP receptor can attenuate asthma(Idzko et al, J. Clin. Invest., 2007, 117:464-472; Jaffar et al, J.Immunol., 2007, 179:6193-6203; Nagao et al, Am. J. Respir. Cell. MoI.Biol., 2003, 29:314-320). It has been shown that an agonist of the IPreceptor can decrease TNF-[alpha] production in type 2 diabetes patients(Fujiwara et al, Exp. Clin. Endocrinol. Diabetes, 2004, 112:390-394;Goya et al, Metabolism, 2003, 52: 192-198). It has been shown that anagonist of the IP receptor can inhibit ischemia-reperfusion injury (Xiaoet al, Circulation, 2001, 104:2210-2215). It has been shown that anagonist of the IP receptor can inhibit restenosis (Cheng et al, Science,2002, 296:539-541). It has been shown that an agonist of the IP receptorcan attenuate pulmonary vascular injury and shock in a rat model ofseptic shock (Harada et al, Shock, 2008, Feb. 21). It has been shownthat an agonist of the IP receptor can reduce the serum levels ofTNF-[alpha] in vivo in patients with rheumatoid arthritis, and this isassociated with improvement in the clinical course of the disease (Gaoet al, Rheumatol. Int., 2002, 22:45-51; Boehme et al, Rheumatol. Int.,2006, 26:340-347).

The compounds as defined in the first aspect disclosed herein providebeneficial reduction of inflammation. The compounds as defined in thefirst aspect disclosed herein provide beneficial reduction of adeleterious inflammatory response associated with an inflammatorydisease. Accordingly, in some embodiments, the present inventionprovides methods for reducing inflammation in a patient in need thereof,comprising administering to the patient a composition comprising an IPreceptor agonist disclosed herein. In some embodiments, the presentinvention provides methods for decreasing IL-12, TNF-[alpha], IL-1[alpha], IL-IjS, BL-6, MIP-Ia or MCP-I production in a patient in needthereof, comprising administering to the patient a compositioncomprising an IP receptor agonist disclosed herein. In some embodiments,the present invention provides methods for decreasing TNF-[alpha]production in a patient in need thereof, comprising administering to thepatient a composition comprising an IP receptor agonist disclosedherein. In some embodiments, the present invention provides methods forincreasing EL-IO production in a patient in need thereof, comprisingadministering to the patient a composition comprising an IP receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for reducing a deleterious inflammatory responseassociated with an inflammatory disease in a patient in need thereof,comprising administering to the patient a composition comprising an IPreceptor agonist disclosed herein. In some embodiments, the presentinvention provides methods for treating an inflammatory disease or asymptom thereof in a patient in need of the treatment comprisingadministering to the patient a composition comprising an IP receptoragonist disclosed herein. In some embodiments, the present inventionprovides methods for treating an inflammatory disease or a symptomthereof in a patient in need of the treatment comprising administeringto the patient a composition comprising an IP receptor agonist disclosedherein. In some embodiments, the present invention provides methods fortreating an inflammatory disease or a symptom thereof in a patient inneed of the treatment comprising administering to the patient acomposition comprising an IP receptor agonist disclosed herein, whereinthe inflammatory disease is selected from the group consisting ofpsoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease,transplant rejection, multiple sclerosis, systemic lupus erythematosus(SLE), ulcerative colitis, ischemia-reperfusion injury, restenosis,atherosclerosis, acne, diabetes (including type 1 diabetes and type 2diabetes), sepsis, chronic obstructive pulmonary disease (COPD), andasthma.

Fibrosis

PGI2 signaling has been shown to play a beneficial role in fibroticdiseases of various organs, including kidney, heart, lung, skin,pancreas and liver, as well as in systemic sclerosis and associatedpathologies. It has been shown that an agonist of the IP receptor canameliorate cardiac fibrosis (Chan E C et al (2010) J Mol Cell Cardiol.April 18; Hirata Y et al (2009) Biomed Pharmacother. 63(10):781-6;Kaneshige T et al (2007) J Vet Med. Sci. 69(12):1271-6). It has beenshown that an agonist of the IP receptor can attenuate renal fibrosis(Takenaka M et al (2009) Prostaglandins Leukot Essent Fatty Acids.80(5-6):263-7). It has been shown that an agonist of the IP receptor canprotect against pulmonary fibrosis in a bleomycin model (Zhu Y et al(2010) Respir Res. 20; 11(1):34). It has been shown that an agonist ofthe IP receptor can suppress the production of connective tissue growthfactor, a key mediator of fibrosis, in scleroderma patients (Stratton Ret al (2001) J Clin Invest. 108(2):241-50). It has been shown that anagonist of the IP receptor can reduce the incidence of digitalulcerations in patients with systemic sclerosis M. Vayssairat (1999) JRheumatol 26:2173-2178. It has been shown that an agonist of the IPreceptor can reduce fingertip necrosis in infants with refractoryRenaud's phenomenon (Shouval D S et al (2008) Clin Exp Rheumatol. 26(3Suppl 49):5105-7). It has been shown that an agonist of the IP receptorcan reduce markers of endothelial activation in patients with systemicsclerosis (Rehberger P et al (2009) Acta Derm Venereol. 89(3):245-9.).It has been shown that an agonist of the IP receptor can reduceseverity, frequency, and duration of Raynaud's attacks in patients withsystemic sclerosis (Torlay et al (1991) Ann Rheum Dis 50, 800-804). Ithas been shown that an agonist of the IP receptor can improve portalhemodynamics in patients with systemic sclerosis and Raynaud'sphenomenon (Zardi et al (2006) In Vivo 20(3):377-80). It has been shownthat an agonist of the IP receptor can inhibit the progression ofpancreatic fibrosis in obese Zucker rats (Sato et al (2010) Diabetes59(4):1092-100).

The IP receptor agonists disclosed herein may provide beneficialanti-fibrotic effects to patients suffering from fibrosis of the kidney,heart, lung, skin, pancreas and liver which can be idiopathic orsecondary to chronic inflammation and systemic sclerosis, for example,and are not limited to the indications described above.

In addition, there is substantial evidence that an agonist of the IPreceptor can improve kidney function in acute and chronic renal failure.It has been shown that an agonist of the IP receptor can restore kidneyfunction in endotoxemia-related acute renal failure (Johannes T et al(2009) Crit. Care Med. 37(4):1423-32). It has been shown that an agonistof the IP receptor can improve renal function in a model of renalischemia/reperfusion injury Sahsivar M O et al (2009) Shock32(5):498-502). It has been shown that an agonist of the IP receptor canprevent contrast agent-induced nephropathy in patients with renaldysfunction undergoing cardiac surgery (Spargias K et al (2009)Circulation 3; 120(18):1793-9.) It has been shown that an agonist of theIP receptor can improve renal function, reduce inflammation andsclerotic changes of the kidney in a model for diabetic nephropathyWatanabe M et al (2009) Am J. Nephrol. 2009; 30(1):1-11).

The IP receptor agonists disclosed herein may provide beneficialimprovement of renal function in patients with acute and chronic kidneyinjury and nephropathies secondary to dye-contrast agents,ischemia-reperfusion injury, systemic inflammation and diabetes forexample, and are not limited to the indications described above.

There is considerable evidence for a causal role of Prostacyclindeficiency in the development of preeclampsia (Mills J L et al (1999)JAMA 282: 356-362; Walsh S W (2004) Prostaglandins Leukot Essent FattyAcids 70: 223-232). The administration of an agonist of the IP receptorhas been shown to lower blood pressure in a rat model of preeclampsia(Zlatnik M G et al (1999) Am J Obstet. Gynecol. 180(5):1191-5).

The IP receptor agonists disclosed herein may provide beneficialimprovement of hemodynamics in patients with preeclampsia.

The IP receptor agonist disclosed herein may provide beneficialtreatment of cystic fibrosis.

The IP receptor agonists disclosed herein may provide chemoprevention.Chemoprevention is the practice of using of drugs, vitamins, ornutritional supplements to reduce the risk of developing, or having arecurrence of cancer. Oral iloprost (Ventavis), an analogue ofprostacyclin, shows promise as a chemopreventive agent for lung cancer.Data supporting IP receptor agonist chemoprevention was presented byPaul Bunn Jr. MD, who is the executive Director of the InternationalAssociation for the Study of Lung Cancer at the American Association forCancer Research 102nd Annual Meeting showed that it significantlyimproved endobronchial dysplasia in former smokers.

PGI2 and other IP receptor agonists, including the compounds as definedin the first aspect, are also useful as co-therapeutic agents for use incombination with second agents, such as organic nitrates and NO-donors,such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate,isosorbide dinitrate, molsidomine or SIN-1, and inhalational NO;compounds that inhibit the degradation of cyclic guanosine monophosphate(cGMP) and/or cyclic adenosine monophosphate (cAMP), such as inhibitorsof phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5, especially PDE 5inhibitors such as sildenafil, vardenafil and tadalafil; NO-independent,but haem-dependent stimulators of guanylate cyclase, such as inparticular the compounds described in WO 00/06568, WO 00/06569, WO02/42301 and WO 03/095451; NO- and haem-independent activators ofguanylate cyclase, such as in particular the compounds described in WO01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO02/070510; compounds which inhibit human neutrophilic elastase, such assivelestat or DX-890 (Reltran); compounds inhibiting the signaltransduction cascade, such as tyrosine kinase and/or serine/threoninekinase inhibitors, in particular imatinib, gefitinib, erlotinib,sorafenib and sunitinib; compounds influencing the energy metabolism ofthe heart, for example and preferably etomoxir, dichloroacetate,ranolazine or trimetazidine; antithrombotic agents, for example andpreferably from the group comprising platelet aggregation inhibitors,anticoagulants or profibrinolytic substances; active substances forlowering blood pressure, for example and preferably from the groupcomprising calcium antagonists, angiotensin II antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, aldosteronesynthase inhibitors, alpha receptor blockers, beta receptor blockers,mineralocorticoid receptor antagonists, Rho-kinase inhibitors anddiuretics; and/or active substances that modify lipid metabolism, forexample and preferably from the group comprising thyroid receptoragonists, inhibitors of cholesterol synthesis, for example andpreferably HMG-CoA-reductase inhibitors or inhibitors of squalenesynthesis, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha,PPAR-gamma and/or PPAR-delta agonists, cholesterol absorptioninhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acidreabsorption inhibitors and lipoprotein(a) antagonists, particularly inthe treatment of PAH or diseases and disorders such as those mentionedhereinbefore, e.g., as potentiators of therapeutic activity of suchdrugs or as a means of reducing required dosaging or potential sideeffects of such drugs.

In particular, an embodiment of this invention is a pharmaceuticalcombination comprising the compounds as defined in the first aspect, ora pharmaceutically acceptable salt thereof, and a second agent whereinthe second agent is a PDEV inhibitor or neutral endopeptidase inhibitor.

The compounds as defined in the first aspect, or a pharmaceuticallyacceptable salt thereof, may be mixed with a second agent in a fixedpharmaceutical composition or it may be administered separately, before,simultaneously with or after the other drug substance.

Accordingly, the invention includes as a further aspect a combination ofan IP receptor activity with osmotic agents (hypertonic saline, dextran,mannitol, Xylitol), ENaC blockers, an anti-inflammatory,bronchodilatory, antihistamine, anti-tussive, antibiotic and/or DNasedrug substance, wherein the IP receptor agonist and the further drugsubstance may be in the same or different pharmaceutical composition.

Suitable antibiotics include macrolide antibiotics, e.g., tobramycin(TOBIT™).

Suitable DNase drug substances include dornase alfa (Pulmozyme™), ahighly-purified solution of recombinant human deoxyribonuclease I(rhDNase), which selectively cleaves DNA. Dornase alfa is used to treatcystic fibrosis.

Other useful combinations of IP receptor agonist with anti-inflammatorydrugs are those with antagonists of chemokine receptors, e.g., CCR-1,CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1,CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such asSchering-Plough antagonists SC-351125, SCH-55700 and SCH-D; Takedaantagonists, such asN-[[4-[[[6,7-dihydro-2-(4-methyl-phenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770); and CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO 00/66558 (particularlyclaim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO04/026873.

Suitable anti-inflammatory drugs include steroids, for examplecorticosteroids. Suitable steroids include budesonide, beclamethasone(e.g. dipropionate), butixocort (e.g. propionate), CHF5188, ciclesonide,dexamethasone, flunisolide, fluticasone (e.g. propionate or furoate),GSK-685698, GSK-870086, LAS40369, methyl prednisolone, mometasone (e.g.furoate), prednisolone, rofleponide, and triamcinolone (e.g. acetonide).In certain preferred embodiments the steroid is long-actingcorticosteroids such as budesonide, ciclesonide, fluticasone ormometasone.

Suitable second active ingredients include β₂-agonists. Suitableβ₂-agonists include arformoterol (e.g. tartrate), albuterol/salbutamol(e.g. racemate or single enantiomer such as the R-enantiomer, or saltthereof especially sulfate), AZD3199, bambuterol, BI-171800, bitolterol(e.g. mesylate), carmoterol, clenbuterol, etanterol, fenoterol (e.g.racemate or single enantiomer such as the R-enantiomer, or salt thereofespecially hydrobromide), flerbuterol, formoterol (e.g. racemate orsingle diastereomer such as the R,R-diastereomer, or salt thereofespecially fumarate or fumarate dihydrate), GSK-159802, GSK-597901,GSK-678007, indacaterol (e.g. racemate or single enantiomer such as theR-enantiomer, or salt thereof especially maleate, acetate or xinafoate),LAS100977, metaproterenol, milveterol (e.g. hydrochloride), naminterol,olodaterol (e.g. racemate or single enantiomer such as the R-enantiomer,or salt thereof especially hydrochloride), PF-610355, pirbuterol (e.g.acetate), procaterol, reproterol, salmefamol, salmeterol (e.g. racemateor single enantiomer such as the R-enantiomer, or salt thereofespecially xinafoate), terbutaline (e.g. sulphate) and vilanterol (or asalt thereof especially trifenatate. In certain preferred embodimentsthe β₂-agonist is an ultra-long-acting β₂-agonist such as indacaterol,or potentially carmoterol, LAS-100977, milveterol, olodaterol, PF-610355or vilanterol. A preferred embodiment one of the second activeingredients is indacaterol (i.e.(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one)or a salt thereof. This is a β₂-adrenoceptor agonist that has anespecially long duration of action (i.e. over 24 hours) and a shortonset of action (i.e. about 10 minutes). This compound is prepared bythe processes described in international patent applications WO2000/75114 and WO 2005/123684. It is capable of forming acid additionsalts, particularly pharmaceutically acceptable acid addition salts. Apreferred salt of(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneis the maleate salt. Another preferred salt is(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-oneacetate. Another preferred salt is(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-onexinafoate.

Suitable bronchodilatory drugs include anticholinergic or antimuscarinicagents, such as aclidinium (e.g. bromide), BEA-2108 (e.g. bromide),BEA-2180 (e.g. bromide), CHF-5407, darifenacin (e.g. bromide),darotropium (e.g. bromide), glycopyrrolate (e.g. racemate or singleenantiomer, or salt thereof especially bromide), dexpirronium (e.g.bromide), iGSK-202405, GSK-203423, GSK-573719, GSK-656398, ipratropium(e.g. bromide), LAS35201, LAS186368, otilonium (e.g. bromide),oxitropium (e.g. bromide), oxybutynin, PF-3715455, PF-3635659,pirenzepine, revatropate (e.g. hydrobromide), solifenacin (e.g.succinate), SVT-40776, TD-4208, terodiline, tiotropium (e.g. bromide),tolterodine (e.g. tartrate), and trospium (e.g. chloride). In certainpreferred embodiments the muscarinic antagonists is long-actingmuscarinic antagonist such as darotropium bromide, glycopyrrolate ortiotropium bromide.

Suitable dual anti-inflammatory and bronchodilatory drugs include dualbeta-2 adrenoceptor agonist/muscarinic antagonists such as GSK-961081(e.g. succinate). and those disclosed in USP 2004/0167167, WO 04/74246and WO 04/74812.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine, as well as those disclosed in JP 2004107299, WO03/099807 and WO 04/026841.

Accordingly, the invention includes as a further aspect a combination ofIP receptor agonist with agents that inhibit ALK5 and/or ALK4phosphorylation of Smad2 and Smad3.

Accordingly, the invention includes as a further aspect a combination ofIP receptor agonist with second agents that are Rho-kinase inhibitors.

Accordingly, the invention includes as a further aspect a combination ofIP receptor agonist with second agents that are tryptophan hydroylase 1(TPH1) inhibitors.

Accordingly, the invention includes as a further aspect a combination ofIP receptor agonist with second agents that are multi-kinase inhibitors,such as imatinib mysilate, Gleevec. Imatinib functions as a specificinhibitor of a number of tyrosine kinase enzymes. It occupies the TKactive site, leading to a decrease in activity. TK enzymes in the bodyinclude the insulin receptor. Imatinib is specific for the TK domain inthe Abelson proto-oncogene, c-kit and PDGF-R (platelet-derived growthfactor receptor).

In an embodiment of this invention, the IP receptor agonist of thisinvention are dosed in combination with a second active agent selectedfrom phosphodiesterase V inhibitors, neutral endopeptidase 1 inhibitors,THP1 inhibitors, multi-kinase inhibitors, endothelin antagonist,diuretic, aldosteron receptor blocker, and endothelin receptor blocker.

In an embodiment of this invention, the IP receptor agonist of thisinvention are dosed in combination with a second active agent selectedfrom phosphodiesterase V inhibitors, neutral endopeptidase 1 inhibitors,THP1 inhibitors, and multi-kinase inhibitors, such as PDGFR or c-Kit.

In another aspect the invention provides a compound as defined in thefirst aspect, or a pharmaceutically acceptable salt thereof, for use inthe manufacture of a medicament for the treatment of a conditionresponsive to IP receptor agonist activity, particularly in PAH.

The agents of the invention may be administered by any appropriateroute, e.g. orally, e.g., in the form of a tablet or capsule;parenterally, e.g., intravenously; by inhalation, e.g., in the treatmentof an obstructive airways disease; intranasally, e.g., in the treatmentof allergic rhinitis; topically to the skin; or rectally. In a furtheraspect, the invention also provides a pharmaceutical compositioncomprising a compound as defined in the first aspect, in free form or inthe form of a pharmaceutically acceptable salt, optionally together witha pharmaceutically acceptable diluent or carrier therefor. Thecomposition may contain a co-therapeutic agent, such as ananti-inflammatory, broncho-dilatory, antihistamine or anti-tussive drugas hereinbefore described. Such compositions may be prepared usingconventional diluents or excipients and techniques known in the galenicart. Thus oral dosage forms may include tablets and capsules.Formulations for topical administration may take the form of creams,ointments, gels or transdermal delivery systems, e.g., patches.Compositions for inhalation may comprise aerosol or other atomizableformulations or dry powder formulations.

When the composition comprises an aerosol formulation, it preferablycontains, e.g., a hydro-fluoro-alkane (HFA) propellant, such as HFA134aor HFA227 or a mixture of these, and may contain one or more co-solventsknown in the art, such as ethanol (up to 20% by weight), and/or one ormore surfactants, such as oleic acid or sorbitan trioleate, and/or oneor more bulking agents, such as lactose. When the composition comprisesa dry powder formulation, it preferably contains, e.g., the compound asdefined in the first aspect or a pharmaceutically acceptable saltthereof having a particle diameter up to 10 microns, optionally togetherwith a diluent or carrier, such as lactose, of the desired particle sizedistribution and a compound that helps to protect against productperformance deterioration due to moisture, e.g., magnesium stearate.When the composition comprises a nebulised formulation, it preferablycontains, e.g., the compound as defined in the first aspect or apharmaceutically acceptable salt thereof either dissolved, or suspended,in a vehicle containing water, a co-solvent, such as ethanol orpropylene glycol and a stabilizer, which may be a surfactant.

Further aspects of the invention include:

-   -   (a) a compound as defined in the first aspect or a        pharmaceutically acceptable salt thereof in inhalable form,        e.g., in an aerosol or other atomisable composition or in        inhalable particulate, e.g., micronised form;    -   (b) an inhalable medicament comprising a compound as defined in        the first aspect or a pharmaceutically acceptable salt thereof        in inhalable form;    -   (c) a pharmaceutical product comprising a compound as defined in        the first aspect in inhalable form in association with an        inhalation device; and    -   (d) an inhalation device containing a compound as defined in the        first aspect or a pharmaceutically acceptable salt thereof in        inhalable form.

Dosages of compounds as defined in the first aspect or apharmaceutically acceptable salt thereof employed in practicing thepresent invention will of course vary depending, e.g., on the particularcondition to be treated, the effect desired and the mode ofadministration. In general, suitable daily dosages for administration byinhalation are of the order of 0.005-10 mg, while for oraladministration suitable daily doses are of the order of 0.05-100 mg.

Pharmaceutical Use and Assay

Compounds of and their pharmaceutically acceptable salts, hereinafterreferred to alternatively as “agents of the invention”, are useful aspharmaceuticals. In particular, the compounds are suitable IP receptoragonist and may be tested in the following assays.

Activity of compounds at the IP receptor (IP receptor) is assessed bymeasuring cAMP accumulation in CHO cells stably expressing the IPreceptor (CHO-IP) using the PerkinElmer AlphaScreen assay. Thistechnology measures the endogenous production of cAMP, in anon-radioactive luminescence proximity homogenous assay. A biologicalreaction occurs between streptavidin coated donor beads, biotinylatedcAMP and anti-cAMP acceptor beads, bringing the donor and acceptor beadsclose enough together so that upon excitation a fluorescence signal isproduced. On production of endogenous cAMP, competition between thebiotinylated cAMP and cellular-derived cAMP causes a reduction in thefluorescent signal. The reduction in signal is proportional to theamount of cAMP being produced, thus it is possible to quantify theamount of cAMP being produced on stimulation with agonist.

Test and reference compounds are prepared at 100×[final] in 100% DMSO,and diluted 1:3 using a Biomek Fx (Beckman Coulter). This is followed byan intermediate dilution to give 5×[final] in assay buffer (HBSScontaining 5 mM HEPES, 0.1% (w/v) BSA). 5 μL of 5×[final] testcompounds, reference compounds and buffer/DMSO control are thentransferred to a 384-well white OptiPlate, containing 20 μL CHO-IP cellsuspension (15,000 cells/well, prepared from frozen), and plate isincubated at room temperature for 1 hour. A cAMP standard curve isconstructed for each experiment (concentration range of 10000 nM to0.001 nM, in assay buffer) and 25 μL of each concentration added to thelast two columns of the assay plate. The incubation is terminated by theaddition of lysis buffer (dH₂O; 0.3% (v v⁻¹) Tween-20) containing 20units mL⁻¹ streptavidin coated donor beads and biotinylated cAMP(pre-incubated for 30 minutes) and 20 units mL⁻¹ anti-cAMP acceptorbeads, which are added to the lysis buffer just before addition to theassay plate. The assay plate is then incubated at room temperature inthe dark, for 60 minutes with gentle shaking, and read on the Envisionplate reader (Perkin Elmer).

The raw data of the reference compounds, test compounds and controls areconverted into cAMP concentrations, using the cAMP standard curve, inGraphPadPrism (GraphPad Software Inc). EC₅₀ as well as maximal values ofthe agonist curves are determined using a 4-parameter logistic equation.The % maximum response values of all test compounds are determined usingthe top of the treprostinil concentration-response curve.

Compounds of the Examples, herein below, generally have EC₅₀ values inthe data measurements described above below 5 μM. Table 1 provides alist of representative compounds with their EC₅₀ value.

TABLE 1 Example EC₅₀ (μM) 1 0.0017 1.1 0.0575 1.2 0.0018 1.3 0.283 1.40.0183 1.5 0.0069 2.1 0.0071 2.2 0.0174 3 0.325 4.1 0.415 4.2 0.0797 50.0007 6 0.0018 7 0.32 8 1.25 9 0.0003 10 0.0005 10.1 0.0024 10.2 0.005610.3 0.0068 10.4 0.0606 10.5 0.0044 10.6 0.0061 10.7 0.0371 10.8 0.002511 0.0016 12 0.66 13 0.0024 14 0.0042 15 0.0036 16 0.0030 17 0.0005

Preparation of Final Compounds General Conditions:

Mass spectra were run on LCMS systems using electrospray ionization.These were either Agilent 1100 HPLC/Micromass Platform Mass Spectrometercombinations or Waters Acquity UPLC with SQD Mass Spectrometer. [M+H]⁺refers to mono-isotopic molecular weights.

NMR spectra were run on open access Bruker AVANCE 400 NMR spectrometersusing ICON-NMR. Spectra were measured at 298K and were referenced usingthe solvent peak.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art. If notdefined, the terms have their generally accepted meanings

ABBREVIATIONS

AcOH acetic acidbr broadBuOH butanolconc. concentratedd doubletDCM dichloromethaneDCE 1,2-dichloroethaneDEAD diethyl azodicarboxylateDIPEA diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxideEt₂O diethyl etherEtOAc ethyl acetateEtOH ethanolh hour(s)HATU O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphateHPLC high pressure liquid chromatographyKOtBu potassium tert-butoxideLCMS liquid chromatography and mass spectrometryMeOH methanolMeCN acetonitrileMS mass spectrometrym multipletmin minutesml milliliter(s)m/z mass to charge ratio

NBS N-bromosuccinimide

NMR nuclear magnetic resonancePdCl₂(dppf)-CH₂Cl₂-adduct [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II)dichloromethanePd(PPh₃)₂Cl₂ bis(triphenylphosphine)palladium(II)dichlorideppm parts per millionPS polymer supportedRt retention timeRT room temperatures singletsat. saturatedSCX-2 strong cation exchange (e.g. Isolute® SCX-2 columns from Biotage)t triplettBuOH tert-butanolTBME methyl-tert-butyl etherTEA triethylamineTHF tetrahydrofuran

Referring to the examples that follow, compounds of the preferredembodiments were synthesized using the methods described herein, orother methods, which are known in the art.

The various starting materials, intermediates, and compounds of thepreferred embodiments may be isolated and purified, where appropriate,using conventional techniques such as precipitation, filtration,crystallization, evaporation, distillation, and chromatography. Unlessotherwise stated, all starting materials are obtained from commercialsuppliers and used without further purification. Salts may be preparedfrom compounds by known salt-forming procedures.

It should be understood that the organic compounds according to thepreferred embodiments may exhibit the phenomenon of tautomerism. As thechemical structures within this specification can only represent one ofthe possible tautomeric forms, it should be understood that thepreferred embodiments encompasses any tautomeric form of the drawnstructure.

If not indicated otherwise, the analytical LCMS conditions are asfollows:

Method 2 minLC_v003

-   Column Waters BEH C18 50×2.1 mm, 1.7.-   Column Temperature 50° C.-   Eluents A: H₂O, B: acetonitrile, both containing 0.1% TFA-   Flow Rate 0.8 ml/min-   Gradient 0.20 min 5% B; 5% to 95% B in 1.30 min, 0.25 min 95% B    2 minLowpH-   Column: Waters Acquity CSH 1.7 μm, 2.1×50 mm-   Temperature: 50° C.-   Mobile Phase: A: Water+0.1% Formic Acid B: Acetonitrile+0.1% Formic    Acid-   Flow rate: 1.0 mL/min-   Gradient: 0.0 min 5% B, 0.2-1.3 min 5-98% B, 1.3-1.55 min 98% B,    1.55-1.6 min 98-5% B    2 minLowpHv01-   Column: Waters Acquity CSH 1.7 μm, 2.1×50 mm-   Temperature: 50° C.-   Mobile Phase: A: Water+0.1% Formic Acid B: Acetonitrile+0.1% Formic    Acid-   Flow rate: 1.0 mL/min-   Gradient: 0.0 min 5% B, 0.2-1.55 min 5-98% B, 1.55-1.75 min 98% B,    1.75-1.8 min 98-5% B    2 minLowpH50v01-   Column: Waters Acquity CSH 1.7 μm, 2.1×50 mm-   Temperature: 50° C.-   Mobile Phase: A: Water+0.1% Formic Acid B: Acetonitrile+0.1% Formic    Acid-   Flow rate: 1.0 mL/min-   Gradient: 0.0 min 50% B, 0.2-1.55 min 50-98% B, 1.55-1.75 min 98% B,    1.75-1.8 min 98-50% B    10 minLowpH-   Column: Waters Acquity CSH 1.7 μm, 2.1×100 mm-   Temperature: 50° C.-   Mobile Phase: A: Water+0.1% Formic Acid B: Acetonitrile+0.1% Formic    Acid-   Flow rate: 0.7 mL/min-   Gradient: 0.0 min 2% B, 0.5-8.0 min 2-98% B, 8.0-9.0 min 98% B,    9.0-9.1 min 98-2% B    Example compounds of the present invention include

Preparation of Final Compounds EXAMPLE 17-(6-Cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Step 1: 6-Chloro-5-iodopyrazin-2-amine

A solution of 6-chloropyrazin-2-amine (10.0 g, 77 mmol) in DMSO (100 ml)was treated with 1-iodopyrrolidine-2,5-dione (20.84 g, 93 mmol). Thereaction mixture was stirred at RT for 2 days and then added to water(800 ml). The pH was adjusted to pH 8-9 using a sat. NaHCO₃ solution andthe resulting suspension was filtered, washing with water (×3) and driedunder vacuum to afford the titled compound as an orange solid;

LC-MS Rt=0.83 mins; [MeCN+H]⁺ 296.0, Method 2 minLowpH.

Step 2: 5,6-Di-p-p-tolylpyrazin-2-amine

A solution of 6-chloro-5-iodopyrazin-2-amine (step 1) (13.74 g, 53.8mmol) in dioxane (300 ml) was degassed with N₂ and treated withp-tolylboronic acid (17.55 g, 129 mmol), K₂CO₃ (22.30 g, 161 mmol) andPdCl₂(dppf)-CH₂Cl₂-adduct (4.39 g, 5.38 mmol). The orange suspension wasstirred at 110° C. for 2 days. After cooling to room temperature thereaction mixture was concentrated under reduced pressure. The crudemixture was absorbed onto silica and purification by chromatographyeluting with 0-60% EtOAc in iso-hexane afforded the titled compound as abeige coloured solid;

LC-MS Rt=1.09 mins; [M+H]⁺ 277.3, Method 2 minLowpH.

Step 3: 3-Bromo-5,6-di-p-tolylpyrazin-2-amine

A solution of 5,6-di-p-tolylpyrazin-2-amine (step 2) (4.94 g, 17.94mmol) in DMSO (40 ml) was treated with N-bromosuccinimide (3.19 g, 17.94mmol). The reaction mixture was stirred at room temperature for 2 hoursto give a beige coloured suspension. The suspension was diluted withwater (700 ml) and the pH was adjusted to pH 8-9 using a sat. NaHCO₃solution. The suspension was filtered, washed with water (×3) and driedunder vacuum to afford the titled compound as a beige coloured solid;

LC-MS Rt=1.39 mins; [M+H]⁺ 356.3, Method 2 minLowpH.

Step 4: 3-(Cyclopropylethynyl)-5,6-di-p-tolylpyrazin-2-amine

A solution of 3-bromo-5,6-di-p-tolylpyrazin-2-amine (step 3) (440 mg,1.24 mmol) in dioxane (5 ml) was degassed with N₂ and treated withtriethylamine (1.558 ml, 11.18 mmol), ethynylcyclopropane (0.210 ml,2.484 mmol), copper(I) iodide (71.0 mg, 0.373 mmol) andPdCl₂(dppf)-CH₂Cl₂-adduct (101 mg, 0.124 mmol). After stirring at roomtemperature for 16 hours, the reaction mixture was concentrated underreduced pressure and dry loaded onto silica using DCM (10 ml).Purification of the crude product by chromatography on silica elutingwith 0-20% EtOAc in iso-hexane afforded the titled compound as a beigecoloured solid;

LC-MS Rt=1.28 mins; [M+H]⁺ 340.5, Method 2 minLowpH.

Step 5: 6-Cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazine

3-(Cyclopropylethynyl)-5,6-di-p-tolylpyrazin-2-amine (step 4)(279 mg,0.822 mmol) in tert-BuOH (10 ml) was treated with potassiumtert-butoxide (184 mg, 1.644 mmol) and heated at reflux for 6 hours. Themixture was diluted with water and extracted with DCM (×3). The combinedorganic extracts were concentrated under reduced pressure andpurification of the crude product by chromatography on silica elutingwith 0-20% EtOAc in iso-hexane afforded the titled compound as a beigecoloured solid;

LC-MS Rt=1.20 mins; [M+H]⁺ 340.5, Method 2 minLowpH.

Step 6: Ethyl7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

6-Cyclopropyl-2,3-di-p-p-tolyl-5H-pyrrolo[2,3-b]pyrazine (step 5) (189mg, 0.557 mmol) in anhydrous DMF (3 ml) degassed with N₂ was treatedwith NaH (60% in mineral oil) (24.50 mg, 0.612 mmol). After stirring atRT for 30 minutes, ethyl 7-bromoheptanoate (0.119 ml, 0.612 mmol) wasadded and stirring continued for 2 hours. The mixture was diluted withwater (50 ml) and the pH was adjusted to pH 1 using 2M HCl. Theresulting mixture was extracted with DCM (×3) and the combined organicextracts were concentrated under reduced pressure. Purification of thecrude product by chromatography on silica eluting with 0-10% EtOAc iniso-hexane afforded the titled compound as a yellow oil;

Rt1.47 mins MS m/z 496.5 [M+H]⁺; Method 2 minLC_v003

1H NMR (400 MHz, d-DMSO) δ 7.27-7.19 (4H, m), 7.12-7.06 (4H, m), 6.31(1H, s), 4.39 (2H, t), 4.02 (2H, m), 2.30 (3H, s), 2.30 (3H, s), 2.21(3H, m), 1.84 (2H, m), 1.49 (2H, m), 1.38-1.27 (4H, br m), 1.17-1.09(5H, br m), 0.91-0.85 (2H, m).

Step 7:7-(6-Cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Ethyl7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(Step 6) (230 mg, 0.464 mmol) in EtOH (4 ml) was treated with 2M NaOH(0.696 ml, 1.392 mmol) and stirred at room temperature for 16 hours. Thereaction mixture was added to water (50 ml) and the pH was adjusted topH 1 by addition of 2M HCl. The resulting suspension was filtered,washed with water (×3) and dried under vacuum. The resultant residue wasdissolved in EtOH (minimal) and excess water added. The resultantaqueous was then extracted with DCM (×3), and the organic solventremoved under reduced pressure. The resultant residue was then taken indiethyl ether, sonicated and the solvent removed under reduced pressure.Further diethyl ether was added, sonicated and the solvent removed underreduced pressure. The resultant residue was dissolved in EtOAc (minimal)and excess iso-hexane was added. The resultant suspension was filtered,the filter cake washed with iso-hexane (×4) and dried to afford thetitled compound as a pale yellow solid.

LC-MS Rt=1.32 mins; [M+H]⁺ 468.6, Method 2 minLowpH.

¹H NMR (400 MHz, DMSO-d6) δ 11.97 (1H, br s), 7.27-7.19 (4H, m),7.14-7.06 (4H, m), 6.32 (1H, s), 4.40 (2H, t), 2.30 (3H, s), 2.30 (3H,s), 2.20 (1H, m), 2.16 (2H, t), 1.85 (2H, m), 1.48 (2H, m), 1.38-1.29(4H, br m), 1.14 (2H, m), 0.89 (2H, m)

The compounds of the following tabulated Examples (Table 1) wereprepared by a similar method to that of Example 1 from by replacingethynylcyclopropane (step 4) with the appropriate commercially availablealkynes. The acids were prepared analogously to Example 1 steps 1-7 andthe esters were prepared analogously to steps 1-6

TABLE 1 Ex. Structure Name [M + H]⁺/NMR 1.1

Ethyl 7-(6- cyclopropyl-2,3-di-p- tolyl-5H-pyrrolo[2,3- b]pyrazin-5-yl)heptanoate LCMS: Rt 1.47 mins MS m/z 496.5 [M + H]+: Method2minLowpH1H 1H NMR(400 MHz, d-DMSO) δ 7.27-7.19 (4H, m), 7.12-7.06 (4H,m), 6.31 (1H, s), 4.39 (2H, t), 4.02 (2H, m), 2.30 (3H, s), 2.30 (3H,s), 2.21 (3H, m), 1.84 (2H, m), 1.49 (2H, m), 1.38- 1.27 (4H, br m),1.17-1.09 (5H, br m), 0.91-0.85 (2H, m). 1.2

7-(6-Isopropyl-2,3-di- p-tolyl-pyrrolo[2,3- b]pyrazin-5-yl)- heptanoicacid LC-MS Rt 1.28 mins MS m/z 470.5 [M + H]+; Method 2minLC_v003 1H NMR(400MHz, d- DMSO) δ 11.94 (1H, br s), 7.24 (4H, m), 7.11 (4H, m), 6.51(1H, s), 4.28 (2H, t), 3.27 (1H, br m), 2.30 (3H, s), 2.30 (3H, s), 2.16(2H, t), 1.79 (2H, br m), 1.47 (2H, br m), 1.37 (3H, d), 1.35 (3H, d),1.32 (4H, br m) 1.3

Ethyl 7-(6-iso propyl- 2,3-di-p-tolyl-5H- pyrrolo[2,3-b]pyrazin- 5-yl)heptano ate LC-MS Rt 1.46 mins MS m/z 497.8/499.3 [M + H]+; Method2minLC_v003 1H NMR (400 MHz, d-DMSO) δ 7.24 (4H, m), 7.11 (4H, m), 6.51(1H, s), 4.28 (2H, t), 4.02 (2H, q), 3.28 (1H, br m), 2.30 (3H, s), 2.30(3H, s), 2.22 (2H, t), 1.79 (2H, br m), 1.49 (2H, br m), 1.37 (3H, d),1.36 (3H, s), 1.34-1.28 (4H, br m), 1.15 (3H, t).

EXAMPLE 1.4 7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acidethyl ester

The titled compound was prepared from2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazine (Intermediate A) analogously toethyl7-(6-cyclopropyl-2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(Example 1 step 6);

LC-MS Rt=1.44 mins; [M+H]⁺ 456.4, Method 2 minLC_v003.

¹H NMR (400 MHz, d-DMSO) δ 7.99 (1H, m), 7.26 (4H, m), 7.12 (4H, m),6.69 (1H, d), 4.29 (2H, t), 4.01 (2H, q), 2.31 (3H, s), 2.31 (3H, s),2.22 (2H, t), 1.85 (2H, br m), 1.49 (2H, br m), 1.36-1.22 (4H, br m),1.15 (3H, t).

EXAMPLE 1.5 7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid

The titled compound was prepared from7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester(Intermediate B) analogously to7-(6-cyclopropyl-2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid (Example 1 step 7);

LC-MS Rt=1.28 mins; [M+H]⁺ 429.4, Method 2 minLC_v003.

1H NMR (400 MHz, d-DMSO) δ 11.97 (1H, br s), 7.99 (1H, d), 7.30-7.22(4H, m), 7.15-7.08 (4H, m), 6.69 (1H, d), 4.30 (2H, t), 2.31 (3H, s),2.31 (3H, s), 2.16 (2H, t), 1.86 (2H, m), 1.47 (2H, m), 1.36-1.22 (4H,br m)

EXAMPLE 2.17-(7-Formyl-2,3di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid

The titled compound was prepared from ethyl7-(7-formyl-2,3di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(Intermediate C) analgously to7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid (Example 1 step 7);

LC-MS Rt=1.22 mins; [M+H]⁺ 456.5, Method 2 minLowpH.

¹H NMR (400 MHz, DMSO-d6) δ 11.96 (1H, s), 10.12 (1H, s), 8.84 (1H, s),7.32-7.27 (4H, m), 7.17-7.13 (4H, m), 4.39 (2H, t), 2.32 (3H, s), 2.31(3H, s), 2.17 (2H, t), 1.92 (2H, m), 1.48 (2H, m), 1.40-1.23 (4H, br m)

EXAMPLE 2.27-(7-(Hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

7-(7-Formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid(Example 2.1) (42 mg, 0.092 mmol) in EtOH (1 ml) was degassed with N₂and treated with sodium borohydride (5.23 mg, 0.138 mmol). Afterstirring at RT for 16 hours, the mixture was added to water (30 ml) andthe pH was adjusted to pH 1 using 2M HCl. The aqueous portion wasextracted with DCM (×3) and the combined extracts were concentratedunder reduced pressure. The crude product was triturated withEtOAc/iso-hexane to afford the titled compound as an orange solid;

LC-MS Rt=1.18 mins; [M+H]⁺ 458.6, Method 2 minLowpH.

¹H NMR (400 MHz, DMSO-d6) δ 11.83 (1H, br s), 7.89 (1H, s), 7.29-7.21(4H, br m), 7.15-7.09 (4H, m), 4.97 (1H, br m), 4.73 (2H, m), 4.27 (2H,m), 2.31 (3H, s), 2.31 (3H, s), 2.14 (2H, m), 1.84 (2H, m), 1.47 (2H,m), 1.37-1.22 (4H, br m)

EXAMPLE 3 Ethyl7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

Ethyl7-(7-Formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(Intermediate C) (47 mg, 0.097 mmol) in EtOH (2 ml) was degassed with N₂treated with sodium borohydride (5.52 mg, 0.146 mmol) was added. Afterstirring at RT for 3 hours, the mixture was diluted with water (30 ml)and the pH was adjusted to pH 1 using 2M HCl. The aqueous portion wasextracted with DCM (×3) and the combined extracts were concentratedunder reduced pressure. Purification of the crude product bychromatography on silica eluting with 0-40% EtOAc in iso-hexane affordedthe titled compound as an orange oil;

LC-MS Rt=1.32 mins; [M+H]⁺ 486.6, Method 2 minLowpH.

¹H NMR (400 MHz, DMSO-d6) δ 7.89 (1H, s), 7.29-7.23 (4H, m), 7.14-7.09(4H, m), 4.95 (1H, t), 4.72 (2H, d), 4.27 (2H, t), 4.02 (2H, m), 2.31(3H, s), 2.31 (3H, s), 2.23 (2H, t), 1.84 (2H, m), 1.49 (2H, m),1.37-1.22 (4H, br m), 1.51 (3H, t).

EXAMPLE 4.1 Ethyl7-(7-((isopropylamino)methyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

Ethyl7-(7-formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(Intermediate C)(50 mg, 0.103 mmol) in DCE (1 ml) was treated withiso-propylamine (0.027 ml, 0.310 mmol) and stirred at RT for 30 minutes.Sodium triacetoxyborohydride (65.7 mg, 0.310 mmol) was added andstirring continued at RT for 16 hours. The mixture was extracted withDCM (30 ml) and the organic extract was washed with water (×2) andconcentrated under reduced pressure to afford the titled compound as anorange oil;

LC-MS Rt=1.06 mins; [M+H]⁺ 527.7, Method 2 minLowpH.

¹H NMR (400 MHz, DMSO-d6): δ 8.61 (1H, br m), 8.12 (1H, s), 7.30-7.25(4H, m), 7.16-7.11 (4H, m), 4.35-4.28 (4H, m), 4.02 (2H, m), 2.31 (3H,s), 2.31 (3H, s), 2.26-2.20 (3H, m), 1.86 (2H, m), 1.49 (2H, m),1.36-1.23 (10H, br m), 1.15 (3H, t).

EXAMPLE 4.27-(7-((Isopropylamino)methyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Ethyl7-(7-((isopropylamino)methyl)-2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(Example 4.1) (53 mg, 0.101 mmol) in EtOH (1 ml) was treated with 2MNaOH (0.151 ml, 0.302 mmol) and stirred at RT for 16 hours. The solventwas removed under reduced pressure and the crude product was dissolvedin water and the pH was adjusted to pH 1 using 2M HCl. The mixture wasextracted with DCM (×3) and the combined organic extracts wereconcentrated under reduced pressure to afford an orange solid. The solidwas suspended in diethyl ether, sonicated and then filtered, rinsing thefilter-cake with diethyl ether (×3). The resultant solid was dried underatmosphere to afford the titled compound as an orange solid.

LC-MS Rt=0.95 mins; [M+H]⁺ 499.7, Method 2 minLowpH.

¹H NMR (400 MHz, DMSO-d6) δ 11.95 (1H, br s), 8.77 (1H, br m), 8.16 (1H,s), 7.31-7.26 (4H, m), 7.17-7.12 (4H, m), 4.39-4.31 (4H, m), 3.39 (1H,m), 2.32 (3H, s), 2.32 (3H, s), 2.17 (2H, t), 1.87 (2H, m), 1.47 (2H,m), 1.37-1.25 (10H, br m)

EXAMPLE 57-(6-Methoxy-2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid

Step 1: Ethyl7-(7-bromo-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester(Intermediate B) (135 mg, 0.296 mmol) in DCM (5 ml) was treated withN-bromosuccinimide (52.7 mg, 0.296 mmol) and the reaction mixture wasstirred at room temperature for 16 hours. The mixture was diluted withDCM (50 ml) and washed with water (×2), brine (×1) and the organicsolvent was removed under reduced pressure. Purification of the crudeproduct by chromatography on silica using a gradient from 0-10% EtOAc iniso-hexane afforded the titled compound as an orange oil;

LC-MS Rt=1.62 mins; [M+H]⁺ 536.4, Method 2 minLowpH.

Step 2:7-(6-Methoxy-2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid

A mixture comprising ethyl7-(7-bromo-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(step 1) (50 mg, 0.094 mmol) in anhydrous MeOH (1 ml) was degassed withN₂ and treated with sodium (10.75 mg, 0.468 mmol). After stirring atroom temperature for 30 minutes, the mixture was heated to 120° C. usingmicrowave radiation for 1 hour. The mixture was diluted with water (20ml) and the pH was adjusted to pH1 using 2M HCl. The aqueous wasextracted with DCM (×3) and the combined organic extracts wereconcentrated under reduced pressure. Purification of the crude productby chromatography on silica eluting with 0-100% EtOAc in iso-hexanefollowed by 10% MeOH in EtOAc afforded the titled compound as an orangesolid;

LC-MS Rt=1.29 mins; [M+H]⁺ 458.4, Method 2 minLC_v003

¹H NMR (400 MHz, DMSO-d6) δ 11.96 (1H, br s), 7.22 (4H, m), 7.09 (4H,m), 5.95 (1H, s), 4.12 (2H, m), 4.10 (3H, s), 2.29 (3H, s), 2.29 (3H,s), 2.15 (2H, t), 1.75 (2H, br m), 1.46 (2H, br m), 1.35-1.23 (4H, br m)

EXAMPLE 6 Ethyl7-(2,3-di-p-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester(Intermediate B) (35 mg, 0.077 mmol) in dry EtOH (1 ml) under nitrogenat RT was treated with ammonium formate (24.22 mg, 0.384 mmol) followedby Pd on carbon (8.18 mg, 7.68 μmol). The resulting black suspension washeated at reflux for 16 hours, overnight. The reaction mixture wascooled to RT and then loaded onto a Celite® (filter material) column.The column was eluted with 1:1 MeOH/DCM and the filtrate concentratedunder reduced pressure. The resultant residue was dissolved in DCM (50ml), washed with water (×2) and the organic solvent removed underreduced pressure. Purification by chromatography on silica eluting with0-30% EtOAc in iso-hexane afforded the titled compound;

LC-MS Rt 1.36 mins MS m/z 458.4 [M+H]⁺; Method 2 minLC_v003

1H NMR (400 MHz, DMSO-d6) δ 7.15 (2H, d), 7.1-7.05 (4H, m), 7.0 (2H, d),4.05 (2H, m), 3.65 (2H, m), 3.35 (2H, m), 3.1 (2H, m), 2.3 (3H, s), 2.25(3H, s), 1.6 (2H, m), 1.5 (2H, m), 1.35-1.2 (6H, m), 1.15 (3H, t).

EXAMPLE 7 5-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)-pentanoicacid

Step 1: 7-(3-Amino-5,6-di-p-tolylpyrazin-2-yl)hept-6-ynoic acid

3-Bromo-5,6-di-p-tolylpyrazin-2-amine (Example 1, step 3) (200 mg, 0.565mmol) in anhydrous dioxane (10 ml), degassed with N₂ was treated withtriethylamine (0.708 ml, 5.08 mmol), hept-6-ynoic acid (0.179 ml, 1.129mmol), copper(I) iodide (32.3 mg, 0.169 mmol) andPdCl₂(dppf)-CH₂Cl₂-adduct (46.1 mg, 0.056 mmol). The reaction mixturewas stirred at room temperature for 16 hours. The resulting mixture wasdiluted with DCM (10 ml) and dry loaded onto silica. Purification bychromatography on silica eluting with 0-100% EtOAc in iso-hexanefollowed by 20% MeOH in EtOAc afforded the titled compound;

LC-MS: Rt 1.25 mins MS m/z 401.3 [M+H]⁺; Method 2 minLC_v003

Step 2: 5-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanoic acid

7-(3-Amino-5,6-di-p-tolylpyrazin-2-yl)hept-6-ynoic acid (step 1) (137mg, 0.343 mmol) in tert-BuOH (3 ml) was treated with potassiumtert-butoxide (154 mg, 1.372 mmol) and stirred at reflux for 3 hours.The mixture was added to water (50 ml) and extracted with DCM (×3). Theorganic solvent was removed under reduced pressure and the crudematerial was dissolved in EtOH (minimal) and excess of water was added.The resulting suspension was sonicated and filtered, rinsing the filtercake with water (×3). Purification of crude product by chromatograpy onsilica eluting with 0-1% MeOH in DCM afforded the titled compound; LC-MSRt 1.10 mins MS m/z 400.2 [M+H]⁺; Method 2 minLC_v003

1H NMR (400 MHz, d-DMSO) δ 12.03 (1H, br s), 11.92 (1H, br s), 7.23 (4H,m), 7.10 (4H, m), 6.41 (1H, m), 2.84 (2H, t), 2.30 (3H, s), 2.30 (3H,s), 2.28 (2H, m), 1.77 (2H, br m), 1.59 (2H, br m)

EXAMPLE 82-(5-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)aceticacid

Step 1: Methyl2-(5-(2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)acetate

5-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanoic acid (Example7) (25 mg, 0.063 mmol) in DMF (1 ml) was treated with DIPEA (0.055 ml,0.313 mmol) and HATU (57.1 mg, 0.150 mmol). After stirring at RT for 15minutes, the mixture was treated with glycine methyl ester hydrochloride(9.43 mg, 0.075 mmol) and stirred at RT for 2 hours. The resultingmixture was diluted with water and the resultant suspension wassonicated and filtered, rinsing the filter cake with water (×3).Purification of crude product by chromatograpy on silica eluting with0-50% EtOAc in iso-hexane followed by 10% MeOH in EtOAc afforded thetitled compound;

LC-MS Rt 1.10 mins MS m/z 471 [M+H]⁺; Method 2 minLC_v003

Step 2:2-(5-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)aceticacid

Methyl2-(5-(2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)acetate(step 1) (17 mg, 0.036 mmol) in THF (1 ml) and water (0.5 ml) wastreated with LiOH. monohydrate (8.12 mg, 0.108 mmol). After stirring atroom temperature for 3 hours, the reaction mixture was treated withwater (20 ml) and the pH adjusted to pH 2 using 2M HCl. The aqueousportion was extracted with DCM (×3) and the combined organic extractswere concentrated under reduced pressure. Purification by reverse phase(C 18) chromatograpy eluting with 0-30% MeCN in water (0.1% TFA)afforded the titled compound;

LC-MS Rt 1.05 mins MS m/z 457.4 [M+H]⁺; Method 2 minLC_v003

1H NMR (400 MHz, d-DMSO) δ 12.51 (1H, br s), 11.92 (1H, s), 8.16 (1H,m), 7.24 (4H, m), 7.1 (4H, m), 6.41 (1H, m), 3.73 (2H, d), 2.84 (2H, t),2.30 (3H, s), 2.30 (3H, s), 2.20 (2H, t), 1.76 (2H, br m), 1.59 (2H, brm)

EXAMPLE 97-(6-Methyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid

Step 1: 3,5-Dibromo-6-chloropyrazin-2-amine

6-Chloropyrazin-2-amine (100 g, 772 mmol) in MeOH (2000 ml) cooled usinga water bath was treated with N-bromosuccinimide (151.2 g, 170 mmol)portionwise over 30 mins, maintaining the reaction temperature between15-20° C. After stirring for 1.5 hours, the mixture was poured carefullyinto a stirred vessel of ice-cooled water (4 litres). The resultantsuspension was stirred for 2 hours in the ice bath, collected byfiltration, rinsing the filter cake with water (800 ml) and dried in avacuum oven to afford the titled compound;

LC-MS Rt 0.99 mins; Method 2 minLowpH

Step 2:5-Bromo-6-chloro-3-(3-(trimethylsilyl)prop-1-ynyl)pyrazin-2-amine

3,5-Dibromo-6-chloropyrazin-2-amine (step 1) (400 mg, 1.392 mmol) in dryTHF (10 ml) was degassed with nitrogen and treated withtrimethyl(prop-2-ynyl)silane (0.218 ml, 1.462 mmol), TEA (0.582 ml, 4.18mmol), CuI (26.5 mg, 0.139 mmol) and Pd(PPh₃)₂Cl₂ (98 mg, 0.139 mmol).After stirring at room temperature for 2 hours, the reaction mixture wasdiluted with water (100 ml) and brine and extracted with DCM (×3). Thecombined organic extracts were concentrated under reduced pressure.Purification of the crude product by chromatography on silica elutingwith 0-20% EtOAc in iso-hexane afforded the titled compound;

LC-MS Rt=1.25 mins; [M+H]⁺ 318/320 Method 2 minLowpH.

Step 3: 2-Bromo-3-chloro-6-methyl-5H-pyrrolo[2,3-b]pyrazine

5-Bromo-6-chloro-3-(3-(trimethylsilyl)prop-1-ynyl)pyrazin-2-amine (step2) (280 mg, 0.879 mmol) in tert-butanol (4 ml) at RT was treated withKOtBu (217 mg, 1.933 mmol) and heated at 60° C. for 2 hours. Thereaction mixture was cooled to room temperature, diluted with water andthe pH adjusted to pH 1 using 2M HCl. The aqueous was extracted with DCM(×3) and the organic solvent removed under reduced pressure to affordthe titled compound:

LC-MS Rt=0.97 mins; [M+H]⁺ 246/248: Method 2 minLowpH.

Step 4: 6-Methyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazine

2-Bromo-3-chloro-6-methyl-5H-pyrrolo[2,3-b]pyrazine (step 3) (183 mg,0.742 mmol) in dioxane (5 ml) was degassed with N₂ and treated withp-tolylboronic acid (242 mg, 1.782 mmol), K₂CO₃ (308 mg, 2.227 mmol) andPdCl₂(dppf)-CH₂Cl₂-adduct (60.6 mg, 0.074 mmol). The reaction mixturewas heated at reflux for 3 hours. After cooling to RT, further portionsof p-tolyl boronic acid (242 mg, 1.782 mmol) andPdCl₂(dppf)-CH₂Cl₂-adduct (60.6 mg, 0.074 mmol) were added and heatingcontinued at reflux for 2 hours. After cooling to RT, the mixture wasdiluted with water (50 ml). The resultant suspension was sonicated andfiltered, rinsing the filter cake with water (×3). Purification of thecrude product by chromatography on silica eluting with 0-30% EtOAc iniso-hexane afforded the titled compound;

LC-MS Rt=1.15 mins; [M+H]⁺ 314/315 Method 2 minLowpH.

Step 5:7-(6-Methyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid

The titled compound was prepared from6-methyl-2,3-di-p-tolyldi-p-tolyl-5H-pyrrolo[2,3-b]pyrazine (Example 9;Step 4) analogously to7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid (Example 1 step 6 and step 7);

LC-MS: Rt 1.28 mins MS m/z 442.7/443.4 [M+H]⁺; Method 2 minLC_v003

¹H NMR (400 MHz, DMSO-d6): δ 11.94 (1H, br s), 7.28-7.21 (4H, m),7.13-7.07 (4H, m), 6.47 (1H, s), 4.25 (2H, t), 2.57 (3H, s), 2.30 (3H,s), 2.30 (3H, s), 2.15 (2H, t), 1.76 (2H, m), 1.46 (2H, m), 1.36-1.25(4H, br m).

EXAMPLE 107-(6-Cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid

Step 1:7-(6-Cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acidethyl ester

A mixture comprising7-(2-bromo-3-chloro-6-cyclopropyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoicacid ethyl ester (Intermediate D) (400 mg, 0.933 mmol) in 1,4-dioxane (8ml) degassed with N₂ was treated with phenylboronic acid (120 mg, 0.980mmol), potassium carbonate (284 mg, 2.052 mmol) andPdCl₂(dppf)-CH₂Cl₂-adduct (76 mg, 0.093 mmol). The reaction mixture wasstirred at 60° C. for 12 hours. After cooling to RT and degassing withN₂, phenylboronic acid (171 mg, 1.399 mmol) andPdCl₂(dppf)-CH₂Cl₂-adduct (76 mg, 0.093 mmol) were added and stirringcontinued at 110° C. for 24 hours. The mixture was treated withice-cooled water and the aqueous was extracted with diethyl ether. Theorganic portion was dried (Na₂SO₄) and concentrated under reducedpressure. Purification of the crude product on silica eluting with 5%EtOAc in iso-hexane afforded the titled compound:

HPLC Rt 5.74 mins: MS m/z 428.1

Step 2:7-(6-Cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid

7-(6-Cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acidethyl ester (step 1) (250 mg, 0.535 mmol) in THF (6 ml) and water (2 ml)was treated with LiOH.monohydrate (45 mg, 1.069 mmol) and stirred atroom temperature for 12 hours followed by heating at 60° C. for 10hours. The mixture was concentrated under reduced pressure. The residuewas dissolved in water and washed with diethyl ether (×1). The aqueouswas acidified using citric acid, and extracted with EtOAc. The organicsolvent was dried (Na₂SO₄) and the solvent was removed under reducedpressure. Purification of the product by chromatography on silicaeluting with 1% MeOH in DCM, followed by further purification usingpreparative HPLC according to the following conditions to afforded thetitled compound;

Column: ZORBAX-150*21.2 MM

Mobile phase: A: 10 mmol ammonium acetate in water; B:1:1MeOH:acetonitrileFlow rate: 30 ml/min.

TIME % B Flow (ml/min)  0.0 60.0 20.0  2.0 60.0 20.0 10.0 90.0 20.0

LCMS: Rt 1.27 mins MS m/z 440.0 [M+H]⁺: Method 2 minLowpH

The compounds of the following tabulated Examples (Table 2) wereprepared by a similar method to that of Example 10 by replacingphenylboronic acid (steps 1 and 2) with the appropriate commerciallyavailable boronic acids.

TABLE 2 Ex. Structure Name [M + H]⁺/NMR 10.1

7-(6-cyclo propyl-2- (4-methoxy phenyl)- 3-(p-tolyl)-5H- pyrrolo[2,3-b]pyrazin-5- yl)heptanoic acid LCMS: Rt 1.28 mins MS m/z 485.4 [M + H]+:Method 2minLowpH 10.2

7-(2,3-bis(4- chlorophenyl)-6- cyclo propyl-5H- pyrrolo[2,3-b]pyrazin-5- yl)heptanoic acid LCMS: Rt 1.42 mins MS m/z 508.3 [M + H]+:Method 2minLowpH 10.3

7-(6-cyclo propyl-2- (4-ethyl phenyl)-3- (p-tolyl)-5H-pyrrolo[2,3-b]pyraz in-5- yl)hep tanoic acid LCMS: Rt 1.39 mins MS m/z 483.4[M + H]+: Method 2minLowpH 10.4

7-(6-cyclo propyl- 2,3-di-m-tolyl-5H- pyrrolo [2,3-b]pyrazin- 5-yl)heptanoic acid LCMS: Rt 1.35 mins MS m/z 469.3 [M + H]+: Method 2minLowpH10.5

7-(6-cyclopropyl-3- (4-ethylphenyl)-2-(p- tolyl)-5H- pyrrolo[2,3-b]pyrazin-5- yl)heptanoic acid LCMS: Rt 1.36 mins; MS m/z 482.6 [M +H]+; 2minLowpH 10.6

7-(6-cyclopropyl-3- (4-methoxyphenyl)- 2-(p-tolyl)-5H- pyrrolo[2.3-b]pyrazin-5- yl)heptanoic acid LCMS: Rt 1.25 mins; MS m/z 484.6[M + H]+;2minLowpH 10.7

7-(6-cyclopropyl-3- (m-tolyl)-2-(p-tolyl)- 5H-pyrrolo[2,3- b]pyrazin-5-yl)heptanoic acid LCMS: Rt 1.31 mins; MS m/z 468.6 [M + H]+; 2minLowpH10.8

7-(6-cyclopropyl-2- (m-tolyl)-3-(p-tolyl)- 5H-pyrrolo[2,3- b]pyrazin-5-yl)heptanoic acid LCMS: Rt 1.32 mins; MS m/z 468.6 [M + H]+; 2minLowpH

EXAMPLE 117-(6-(2-Hydroxyethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Step 1: 4-(3-Amino-5,6-di-p-tolylpyrazin-2-yl)but-3-yn-1-ol

The title compound was prepared analogously to7-(3-amino-5,6-di-p-tolylpyrazin-2-yl)hept-6-ynoic acid (Ex 7 step 1) byreplacing hept-6-ynoic acid with but-3-yn-1-ol;

LCMS: Rt 1.11 mins MS m/z 344 [M+H]+ Method 2 minLowpH

Step 2: 2-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethanol

The title compound was prepared from4-(3-amino-5,6-di-p-tolylpyrazin-2-yl)but-3-yn-1-ol (step 1) analogouslyto 5-(2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanoic acid (Ex 7,step 2);

LCMS: Rt 1.04 mins MS m/z 344 [M+H]+: Method 2 minLowpH

Step 3: 2-(2,3-Dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate

2-(2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethanol (step 2) (73 mg,0.213 mmol) in dry THF (2 ml) at RT was treated with DIPEA (0.082 ml,0.468 mmol) and acetyl chloride (0.018 ml, 0.255 mmol). After stirringfor 16 hours at RT, the mixture was added to water (30 ml) and extractedwith DCM (×3). The combined organic extracts were passed through a phaseseparating column and concentrated under reduced pressure. The crudeproduct was purified by chromatography on silica eluting with 0-40%EtOAc/iso-hexane to afford the title compound,2-(2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate;

LCMS: Rt 1.15 mins MS m/z 386.6 [M+H]+Method 2 minLowpH

2-(5-Acetyl-2,3-d-ip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetatewas also isolated as a by-product.

Step 4: Ethyl7-(6-(2-acetoxyethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

2-(2,3-Dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)ethyl acetate (step 3)(12 mg, 0.031 mmol) was dissolved in dry DMF (1 ml) at RT and treatedwith K₂CO₃ (12.91 mg, 0.093 mmol) and ethyl 7-bromoheptanoate (0.012 ml,0.062 mmol). The resulting brown suspension was stirred at RT for 16hours. The mixture was then heated at 60° C. for 5 hours and aftercooling to RT, stirred overnight. The mixture was added to water (30 ml)and extracted with DCM (×3). The combined organic extracts were passedthrough a phase separating column and concentrated under reducedpressure to afford the title compound;

LCMS: Rt 1.40 mins MS m/z 542.7 [M+H]+; Method 2 minLowpH

Step 5:7-(6-(2-Hydroxyethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Ethyl7-(6-(2-acetoxyethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(step 4) (17 mg, 0.031 mmol) in EtOH (1 ml) at RT was treated with 2MNaOH (0.047 ml, 0.094 mmol) and stirred at RT for 4 hours. Further 2MNaOH (0.047 ml, 0.094 mmol) was added and the mixture was stirred at RTfor 16 hours overnight. Further 2M NaOH (0.047 ml, 0.094 mmol) was addedand the orange RM was stirred at RT overnight. The resulting mixture wasadded to water (30 ml) and the pH was adjusted to pH1 by addition of 2MHCl. The aqueous was extracted with DCM (×4) and the combined extractswere passed through a phase separating column and concentrated underreduced pressure to afford an orange oil. The oil was dissolved in EtOAcand an excess of iso-hexane was added. The resulting suspension wassonicated and removed by filtration. The filtrate was concentrated underreduced pressure and the crude product was dissolved in DCM (minimal)and loaded onto a S±20 mm×20 mm preparative TLC plate. Using a solventsystem of 10% MeOH in DCM (200 ml) the TLC plate was eluted and theappropriate strip of Si on the plate was scrapped off the plate. The Siwas suspended in 10% MeOH/DCM and sonicated. The suspension wasfiltered, rinsing the solid with 10% MeOH/DCM. The filtrate wasconcentrated under reduced pressure to afford the title compound;

LCMS: Rt 1.16 mins MS m/z 472.1/473.4 [M+H]+Method 2 minLowpH

1H NMR (400 MHz, d-DMSO) δ 11.96 (1H, br s), 7.28-7.20 (4H, br m),7.14-7.08 (4H, br m), 6.52 (1H, s), 4.91 (1H, br m), 4.29 (2H, m), 3.83(2H, m), 3.05 (2H, m), 2.30 (3H, s), 2.30 (3H, s), 2.16 (2H, m),1.81-1.73 (2H, br m), 1.52-1.43 (2H, br m), 1.37-1.27 (4H, br m)

EXAMPLE 125-(6-Cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)pentanoicacid

The title compound was prepared analogously to Example 1 by replacingethyl 7-bromoheptanoate (step 6) with ethyl 5-bromopentanoate;

LCMS: Rt 1.42 mins MS m/z 441.5 [M+H]+;Method 2 minLowpHv01

1H NMR (400 MHz, d-DMSO) δ 12.01 (1H, br s), 7.28-7.19 (4H, br m),7.13-7.07 (4H, br m), 6.32 (1H, s), 4.41 (2H, m), 2.34-2.27 (2H, br m),2.31 (3H, s), 2.31 (3H, s), 2.23-2.16 (1H, br m), 1.92-1.83 (2H, br m),1.58-1.49 (2H, br m), 1.16-1.10 (2H, br m), 0.91-0.87 (2H, br m)

EXAMPLE 136-(6-Cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)hexanoicacid

The title compound was prepared analogously to Example 1 by replacingethyl 7-bromoheptanoate (step 6) with ethyl 6-bromohexanoate;

LCMS: Rt 1.43 mins MS m/z 454.2/455.5 [M+H]+: Method 2 minLowpHv01.

1H NMR (400 MHz, d-DMSO) δ 11.98 (1H, br s), 7.28-7.19 (4H, br m),7.13-7.07 (4H, br m), 6.32 (1H, s), 4.40 (2H, m), 2.30 (3H, s), 2.30(3H, s), 2.23-2.17 (3H, br m), 1.90-1.82 (2H, br m), 1.62-1.54 (2H, brm), 1.38-1.29 (2H, br m), 1.16-1.11 (2H, br m), 0.91-0.87 (2H, br m).

EXAMPLE 147-(7-(Methoxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Ethyl7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(Example 3) (50 mg, 0.103 mmol) in dry DMF (1 ml) under nitrogen wastreated with NaH (60% in mineral oil) (4.53 mg, 0.113 mmol) and theresulting mixture was stirred at RT for 15 minutes. Methyl iodide (7.08μl, 0.113 mmol) was added and stirring continued at RT overnight. Themixture was added to water (30 ml) and the pH was adjusted to pH1 byaddition of 2M HCl. The aqueous was extracted with DCM (×3) and thecombined organic portions were passed through a phase separating columnand concentrated under reduced pressure. The crude product was purifiedby chromatography on silica eluting with 0-50% EtOAc/iso-hexane. Furtherpurification was carried out by dissolving the product in DCM (minimal)and loading onto a 20 cm×20 cm preparative TLC plate. The plate was runusing a solvent system of 67% EtOAc in iso-hexane (300 ml) and theappropriate strip of silica was scrapped off the plate. The Si wassuspended in 10% MeOH/DCM and sonicated. The suspension was filtered,rinsing the solid with 10% MeOH/DCM. The filtrate was concentrated underreduced pressure to afford the title compound;

LCMS: Rt 1.43 mins MS m/z 473.8 [M+H]+: Method 2 minLowpHv01

1H NMR (400 MHz, d-DMSO) δ 12.03 (1H, br s), 8.01 (1H, s), 7.29-7.22(4H, br m), 7.14-7.10 (4H, br m), 4.62 (2H, s), 4.28 (2H, m), 3.31 (3H,s), 2.31 (3H, s), 2.31 (3H, s), 2.14 (2H, m), 1.88-1.82 (2H, br m), 1.49(2H, br m), 1.36-1.21 (4H, br m)

EXAMPLE 157-(6-oxo-2,3-dip-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Step 1:7-(7,7-Dibromo-6-oxo-2,3-di-p-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid (Example1.5) (90 mg, 0.211 mmol) in tert-butanol (3 ml) and water (0.5 ml) wastreated with NBS (112 mg, 0.632 mmol) and the resulting brown mixturewas stirred at RT for 18 hours. The mixture was diluted with water (50ml) and the pH was adjusted to pH 1 using 2M HCl. The aqueous wasextracted with DCM (×3), passing the organics through a phase separatingcolumn. The organic solvent was removed under reduced pressure to affordthe title compound as a mixture with mono-bromo and unbrominatedcompounds;

LCMS: Rt 1.54 mins MS m/z 602.1 [M+H]+; Method 2 minLowpHv01

Step 2:7-(6-oxo-2,3-di-p-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

7-(7,7-Dibromo-6-oxo-2,3-di-p-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid (mixture from step 1) (127 mg, 0.211 mmol) in dry THF (5 ml) undernitrogen was treated with 10% Pd(C) (22.48 mg, 0.021 mmol) and themixture was stirred at RT under an atmosphere of hydrogen for 16 hours.The resulting mixture was filtered through Celite® and washed throughwith DCM. The filtrate was concentrated under reduced pressure andpurification was carried out by chromatography on silica eluting with0-100% EtOAc in iso-hexane. Further purification was carried out bydissolving the product in DCM (minimal) and loading onto a 20 cm×20 cmpreparative TLC plate. The plate was run using a solvent system of 75%EtOAc in iso-hexane (300 ml) and the appropriate strip of Si wasscrapped off the plate. The silica was suspended in 10% MeOH/DCM andsonicated. The suspension was filtered, rinsing the solid with 10%MeOH/DCM. The filtrate was concentrated under reduced pressure to affordthe title compound;

LCMS: Rt 1.34 mins MS m/z 444.5 [M+H]+Method 2 minLowpHv01

1H NMR (400 MHz, d-DMSO) δ 11.96 (1H, br s), 7.25 (2H, m), 7.20 (2H, m),7.16-7.09 (4H, br m), 3.83 (2H, m), 3.74 (2H, m), 2.30 (3H, s), 2.29(3H, s), 2.18 (2H, m), 1.73-1.64 (2H, br m), 1.52-1.44 (2H, br m),1.36-1.28 (4H, br m)

EXAMPLE 167-(2,3-Dip-tolyl-6-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Step 1: 5,6-Dip-tolyl-3-(3,3,3-trifluoroprop-1-ynyl)pyrazin-2-amine

A solution of 3-bromo-5,6-di-p-tolylpyrazin-2-amine (Ex 1, step 3) (200mg, 0.565 mmol) in dioxane (4 ml) bubbled with nitrogen was treated withtributyl(3,3,3-trifluoroprop-1-ynyl)stannane (238 mg, 0.621 mmol) andPdCl₂(dppf)-CH₂Cl₂-Adduct (46.1 mg, 0.056 mmol). The resulting mixturewas heated at 140° C. for 1 hour using microwave radiation. Aftercooling to RT, the mixture was concentrated under reduced pressure. Thecrude residue was dissolved in DCM and loaded onto a 25 g Silica column.Purification by chromatography on silica eluting with 0-5% EtOAc iniso-hexane afford the title compound;

LCMS: Rt 1.51 mins MS m/z 368.5 [M+H]+; Method 2 minLowpHv01

Step 2: 2,3-Di-p-tolyl-6-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared from5,6-di-p-tolyl-3-(3,3,3-trifluoroprop-1-ynyl)pyrazin-2-amine (step 1)analogously to Ex 1 step 5;

LCMS: Rt 1.45 mins MS m/z 368.3 [M+H]+Method 2 minLowpHv01

Step 3: Ethyl7-(2,3-dip-tolyl-6-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

The title compound was prepared from2,3-di-p-tolyl-6-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazine (step 2)analogously to Ex 1 step 6;

LCMS: Rt 1.73 min MS m/z 524.4 [M+H]+: Method 2 minLowpHv01

Step 4:7-(2,3-Di-p-tolyl-6-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

The title compound was prepared from ethyl7-(2,3-di-p-tolyl-6-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(step 3) analogously to Ex 1 step 7;

LCMS: Rt 1.57 mins MS m/z 496.6 [M+H]+; Method 2 minLowpHv01

EXAMPLE 177-(6,7-Diethyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

Step 1: 6,7-Diethyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazine

Reference: J Org. Chem., Vol. 63, No. 22, 1998, 7652

A solution of 3-bromo-5,6-di-p-tolylpyrazin-2-amine (Ex 1, step 3) (20mg, 0.056 mmol) in DMF (1 ml) bubbled with nitrogen was treated withhex-3-yne (0.013 ml, 0.113 mmol), palladium acetate (0.634 mg, 2.82μmol), lithium chloride (2.393 mg, 0.056 mmol) and K₂CO₃ (39.0 mg, 0.282mmol). The resulting mixture was heated at 120° C. for 30 min usingmicrowave radiation. In parallel, a separate identical reaction mixturewas prepared and heated thermally at 120° C. for 1 hour. After coolingto RT, the two reaction mixtures were combined in water (50 ml). Theaqueous was extracted with EtOAc (×3). The combined organic extractswere washed sequentially with water (×1) and brine (×1), dried (MgSO4),filtered and concentrated under reduced pressure. Purification of thecrude product by chromatography on silica eluting with 0-10% EtOAc iniso-hexane afforded the title compound;

LCMS: Rt 1.50 mins MS m/z 356.3 [M+H]+Method 2 minLowpHv01

Step 2: Ethyl7-(6,7-diethyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

A solution of 6,7-diethyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazine(step 1) (14 mg, 0.039 mmol) in dry DMF (1 ml) under nitrogen wastreated with NaH (1.733 mg, 0.043 mmol). The resulting mixture wasstirred at RT for 20 minutes and treated with ethyl 7-bromoheptanoate(8.44 μl, 0.043 mmol). After stirring at RT for 3 hours, the mixture wasadded to water and the pH was adjusted to pH1 using 2M HCl. The aqueouswas extracted with EtOAc (×3) and the combined organic extracts weresequentially washed with water (×1) and brine (×1), dried (MgSO4),filtered and concentrated under reduced pressure to afford the titlecompound (with trace hydrolysis acid product present);

LCMS: Rt 1.57 mins MS m/z 514.6 [M+H]+Method 2 minLowpH50v01

Step 3:7-(6,7-Diethyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoicacid

The title compound was prepared from ethyl7-(6,7-diethyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(step 2) analogously to Ex 1 step 7;

LCMS: Rt 1.63 mins MS m/z 484.6 [M+H]+Method 2 minLowpHv01

1H NMR (400 MHz, d-DMSO) δ 11.98 (1H, br s), 7.27-7.21 (4H, br m),7.14-7.08 (4H, br m), 4.26-4.20 (2H, br m), 2.95-2.87 (2H, br m),2.81-2.74 (2H, br m), 2.31 (3H, s), 2.31 (3H, s), 2.17-2.12 (2H, br m),1.81-1.73 (2H, br m), 1.52-1.43 (2H, br m), 1.35-1.21 (10H, br m).

Preparation of Intermediates: Intermediate A2,3-Di-p-tolyl5H-pyrrolo[2,3-b]pyrazine

Step 1: 6-Chloro-5-iodopyrazin-2-amine

A solution of 6-chloropyrazin-2-amine (10.0 g, 77 mmol) in DMSO (100 ml)was treated with 1-iodopyrrolidine-2,5-dione (20.84 g, 93 mmol). Thereaction mixture was stirred at RT for 2 days and then added to water(800 ml). The pH was adjusted to pH 8-9 using a sat. NaHCO₃ solution andthe resulting suspension was filtered, washing with water (×3) and driedunder vacuum to afford the titled compound as an orange solid;

LC-MS Rt=0.83 mins; [MeCN+H]⁺ 296.0, Method 2 minLowpH.

Step 2: 5,6-Di-p-tolylpyrazin-2-amine

A solution of 6-chloro-5-iodopyrazin-2-amine (step 1) (13.74 g, 53.8mmol) in dioxane (300 ml) was degassed with N₂ and treated withp-tolylboronic acid (17.55 g, 129 mmol), K₂CO₃ (22.30 g, 161 mmol) andPdCl₂(dppf)-CH₂Cl₂-adduct (4.39 g, 5.38 mmol). The orange suspension wasstirred at 110° C. for 2 days. After cooling to room temperature thereaction mixture was concentrated under reduced pressure. The crudemixture was absorbed onto silica and purification by chromatographyeluting with 0-60% EtOAc in iso-hexane afforded the titled compound as abeige coloured solid;

LC-MS Rt=1.09 mins; [M+H]⁺ 277.3, Method 2 minLowpH.

Step 3: 3-Bromo-5,6-di-p-tolylpyrazin-2-amine

A solution of 5,6-di-p-tolylpyrazin-2-amine (step 2) (4.94 g, 17.94mmol) in DMSO (40 ml), was treated with N-bromosuccinimide (3.19 g,17.94 mmol). The reaction mixture was stirred at room temperature for 2hours to give a beige coloured suspension. The suspension was dilutedwith water (700 ml) and the pH was adjusted to pH 8-9 using a sat.NaHCO₃ solution. The suspension was filtered, washed with water (×3) anddried under vacuum to afford the titled compound as a beige colouredsolid;

LC-MS Rt=1.39 mins; [M+H]⁺ 356.3, Method 2 minLowpH.

Step 4: 5,6-Di-p-tolyl-3-((trimethylsilyl)ethynyl)pyrazin-2-amine

A solution of 3-bromo-5,6-di-p-tolylpyrazin-2-amine (step 3) in drydioxane (10 ml) was degassed with N₂ and treated with triethylamine(1.062 ml, 7.62 mmol), ethynyltrimethylsilane (0.239 ml, 1.694 mmol),copper(I) iodide (48.4 mg, 0.254 mmol) and PdCl₂(dppf)-CH₂Cl₂-adduct(69.2 mg, 0.085 mmol). After stirring at room temperature for 5 hours,the reaction mixture was added to water (50 ml) and extracted with DCM(×3). The organic extracts were passed through a phase separating columnand brine was added to aid separation. The solvent was removed underreduced pressure and purification of the crude product by chromatographyon silica eluting with 0-5% EtOAc in iso-hexane afforded the titledcompound;

LC-MS Rt=1.50 mins; [M+H]⁺ 372, Method 2 minLC_v003.

Step 5: 2,3-Di-p-tolyl-5H-pyrrolo[2,3-b]pyrazine

5,6-Di-p-tolyl-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (step 4) (170mg, 0.458 mmol) in tert-BuOH (5 ml) at RT was treated with potassiumtert-butoxide (205 mg, 1.830 mmol) and heated at reflux for 3 hours.After cooling to RT, conc. HCl (0.5 ml, 16.46 mmol) was added and themixture was heated at reflux for 3 hours and stirred at RT overnight.The mixture was added to water (100 ml) and the pH was adjusted to pH 10using 2M NaOH. The aqueous portion was extracted with DCM (×3) and thecombined organic extracts were passed through a phase separating column.The solvent was removed under reduced pressure and purification of thecrude product by chromatography on silica eluting with 0-20% EtOAc iniso-hexane afforded the titled compound;

LC-MS Rt=1.17 mins; [M+H]⁺ 300, Method 2 minLC_v003.

1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, d-DMSO) δ 12.06 (1H, br s),7.91 (1H, m), 7.25 (4H, m), 7.11 (4H, m), 6.67 (1H, d), 2.30 (3H, s),2.30 (3H, s)

Intermediate B 7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoicacid ethyl ester

The titled compound was prepared from2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazine (Intermediate A) analogously toethyl7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate(Example 1 step 6);

LC-MS Rt=1.44 mins; [M+H]⁺ 456, Method 2 minLC_v003.

¹H NMR (400 MHz, d-DMSO) δ 7.99 (1H, m), 7.26 (4H, m), 7.12 (4H, m),6.69 (1H, d), 4.29 (2H, t), 4.01 (2H, q), 2.31 (3H, s), 2.31 (3H, s),2.22 (2H, t), 1.85 (2H, br m), 1.49 (2H, br m), 1.36-1.22 (4H, br m),1.15 (3H, t).

Intermediate C Ethyl7-(7-Formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

Step 1: Ethyl7-(7-formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate

A mixture comprising7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester(Intermediate B) (479 mg, 1.051 mmol) in anhydrous DMF (1 ml) wasdegassed with N₂ and treated dropwise with POCl₃ (0.147 ml, 1.577 mmol).The mixture was stirred at room temperature for 3 hours and treated witha further portion of POCl₃ (0.147 ml, 1.577 mmol). After stirring at RTfor 16 hours, the mixture was partitioned between water (100 ml) andEtOAc (20 ml) and the pH of the bi-phasic solution was adjusted to pH8-9 using sat. NaHCO₃ solution. The aqueous portion was extracted withEtOAc (×3) and the combined organic extract were washed with water (×1),brine (×1), dried over MgSO₄ and filtered and concentrated under reducedpressure to afford the titled compound as a brown oil;

LC-MS Rt=1.37 mins; [M+H]⁺ 484.6, Method 2 minLowpH.

Intermediate D7-(2-Bromo-3-chloro-6-cyclopropyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoicacid ethyl ester

Step 1: 2-Bromo-3-chloro-6-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine

The titled compound was prepared from 6-chloropyrazin-2-amine(commercial) analogously to2-bromo-3-chloro-6-methyl-5H-pyrrolo[2,3-b]pyrazine (Example 9 step 1 tostep 3) by replacing trimethyl(prop-2-ynyl)silane (step 2) withethynylcyclopropane.

Step 2:7-(2-Bromo-3-chloro-6-cyclopropyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoicacid ethyl ester

2-Bromo-3-chloro-6-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine (step 1) (1.0g, 3.696 mmol) in DMF (10 ml), cooled to 0° C. and degassed with argon,was treated with potassium carbonate (1.53 g, 10.88 mmol) and stirredfor 5 minutes. The reaction mixture was then treated with ethyl7-bromoheptanoate (960 mg, 4.066 mmol) and stirred at room temperaturefor 16 hours. Saturated aqueous ammonium chloride solution was addedslowly at 0° C. and the mixture was extracted with diethyl ether. Theorganic portion was dried (Na₂SO₄), and the solvent was removed underreduced pressure. Purification of the crude product by chromatography onneutral alumina eluting with 0-2% EtOAc in iso-hexane afforded thetitled compound;

MS: m/z [M+H]⁺ 428

HPLC: Rt 5.77 mins

Prophetic Compounds

The following compounds may be prepared according to similar methods asdisclosed herein.

Structure Name

7-(6-cyclopropyl-2,3-di- m-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid

7-(6-cyclopropyl-2-(4- methoxyphenyl)-3-(p- tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid

7-(7-methyl-2,3-di-p- tolyl-5H-pyrrolo[2,3- b]pyrazin-5-yl)heptanoicacid

7-(7-(3-hydroxyphenyl)- 2,3-di-p-tolyl-5H- pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid

7-(7-(methylcarbamoyl)- 2,3-di-p-tolyl-5H- pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid

7-(7-((2- hydroxyethyl)carbamoyl)- 2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5- yl)heptanoic acid

7-(6-(2-hydroxypropan-2- yl)-2,3-di-p-tolyl-5H- pyrrolo[2,3-b]pyrazin-5-yl)heptanoic acid

6-Cyclopropyl-5-[6-(1H- tetrazol-5-yl)-hexyl]-2,3-di-p-tolyl-5H-pyrrolo[2,3- b]pyrazine

6-Methyl-5-[6-(1H- tetrazol-5-yl)-hexyl]-2,3- di-p-tolyl-5H-pyrrolo[2,3-b]pyrazine

6-Methoxy-5-[6-(1H- tetrazol-5-yl)-hexyl]-2,3-di-p-tolyl-5H-pyrrolo[2,3- b]pyrazine

6-Isopropyl-5-[6-(1H- tetrazol-5-yl)-hexyl]-2,3-di-p-tolyl-5H-pyrrolo[2,3- b]pyrazine

6-Cyclopropyl-5-[5-(1H- tetrazol-5-yl)-pentyl]-2,3-di-p-tolyl-5H-pyrrolo[2,3- b]pyrazine

6-Methyl-5-[5-(1H- tetrazol-5-yl)-pentyl]-2,3-di-p-tolyl-5H-pyrrolo[2,3- b]pyrazine

6-Methoxy-5-[5-(1H- tetrazol-5-yl)-pentyl]-2,3-di-p-tolyl-5H-pyrrolo[2,3- b]pyrazine

6-Isopropyl-5-[6-(1H- tetrazol-5-yl)-pentyl]-2,3-di-p-tolyl-5H-pyrrolo[2,3- b]pyrazine

Consistory Clauses Embodiment 1

A compound represented by formula

or a pharmaceutically acceptable salt thereof, wherein

A is N or CR;

R′ is H, C₁-C₈ alkyl optionally substituted by one or more halogenatoms;R¹ is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; —(C₂-C₄ alkyl)-NR¹⁹R²¹ and C₃-C₇ cycloalkyl; or

R¹ is —X—Y; or R¹ is —W—R⁷—X—Y; or R¹ is —S(O)₂—X—Y; or R¹ is—S(O)₂—W—R⁷—X—Y;

R² is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; C₁-C₄ alkoxy; —(C₀-C₄ alkyl)-NR¹⁹R²¹ and C₃-C₇cycloalkyl; or

R² is —X—Y; or R² is —W—R⁷—X—Y; or R² is —S(O)₂—X—Y; or R² is—S(O)₂—W—R⁷—X—Y;

R^(2a) is selected from H; C₁-C₈ alkyl optionally substituted by one ormore halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; and C₃-C₇ cycloalkyl; orR² and R^(2a) taken together are oxo;wherein one of R¹ and R² is —X—Y, —W—R⁷—X—Y, —S(O)₂—X—Y; or—S(O)₂—W—R⁷—X—Y;R³ is independently selected from H; C₁-C₈ alkyl optionally substitutedby one or more halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl orC₃-C₇ cycloalkyloxy; —OH; OR′; —(C₀-C₄alkyl)-NR¹⁹R²¹; CN; halogen;—(C₀-C₄alkyl)-C₆-C₁₄aryl; —(C₀-C₄alkyl)-4 to 14 membered heteroaryl;—C(═O)H; —C(═O)OH; —C(═O)NR¹⁹R²¹ and C₃-C₇ cycloalkyl, wherein the aryland heteroaryl are optionally substituted by one or more substituentsindependently selected from OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogens andC₁-C₄ haloalkyl;R^(3a) is selected from H; C₁-C₈ alkyl optionally substituted by one ormore halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; and C₃-C₇ cycloalkyl; orR³ and R^(3a) taken together are oxo;R⁵ and R⁶ are independently selected from —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and—(C₀-C₄ alkyl)-4 to 14 membered heteroaryl, wherein the aryl andheteroaryl are each optionally substituted by one or more Zsubstituents;W is C₁-C₈ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;X is C₁-C₈ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;Y is carboxy, C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or—CONH—S(O)_(q)—R^(x), whereinR^(x) is phenyl, benzyl or —NR¹⁹R²¹;q is 0, 1 or 2;R⁷ is a divalent moiety represented by —O—, —S—, —NHC(O)—, —CH₂═CH₂—,—C₆-C₁₄ aryl-D-; -3 to 14 membered heterocyclyl-D-, wherein theheterocyclyl contains at least one heteroatom selected from N, O and S,wherein D is O, S, NH or not present;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups, C₁-C₆ alkoxy optionallysubstituted by one or more halogen, C₁-C₆ alkoxy optionally substitutedby C₁-C₄ alkoxy, NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹, (SO₂)R²¹, NR¹⁸C(O)R²¹,C(O)NR¹⁹R²¹, NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹,SR¹⁹, OR¹⁹, oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclyl,wherein the heterocyclyl contains at least one heteroatom selected fromN, O and S;R¹⁸ is independently H or C₁-C₆ alkyl;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; —(C₁-C₄ alkyl)-carboxy; (C₀-C₄ alkyl)-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; (C₀-C₄ alkyl)-3- to 14-membered heterocyclyl,the heterocyclyl including one or more heteroatoms selected from N, Oand S, optionally substituted by one or more groups selected fromhalogen, oxo, C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-memberedheterocyclyl, the heterocyclyl including one or more heteroatomsselected from N, O and S, optionally substituted by one or more groupsselected from halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl;wherein the alkyl groups are optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C(O)NH₂, C(O)NHC₁-C₆ alkyl orC(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclyl, the heterocyclyl including one or morefurther heteroatoms selected from N, O and S, the heterocyclyl beingoptionally substituted by one or more substituents selected from OH;halogen; aryl; 5- to 10-membered heterocyclyl including one or moreheteroatoms selected from N, O and S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl;C₁-C₆ alkyl optionally substituted by one or more halogen atoms; C₁-C₆alkoxy optionally substituted by one or more OH groups or C₁-C₄ alkoxy;and C(O)OC₁-C₆ alkyl, wherein the aryl and heterocyclyl substituentgroups are themselves optionally substituted by C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ alkoxy.

Embodiment 2

The compound according to embodiment 1, wherein

wherein one of R¹ and R² is —X—Y, —W—R⁷—X—Y, —S(O)₂—X—Y; or—S(O)₂—W—R⁷—X—Y;

W is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

X is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

Y is carboxy, C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or—CONH—S(O)_(q)—R^(x), wherein R^(x) is phenyl, benzyl or —NR¹⁹R²¹;

q is 2;

R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O; and

R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl.

Embodiment 3

The compound according to embodiment 1 or 2, wherein

one of R¹ and R² is —X—Y; or —W—R⁷—X—Y;

W is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

X is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

Y is carboxy, C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or—CONH—S(O)_(q)—R^(x),

wherein R^(x) is phenyl, benzyl or —NR¹⁹R²¹;

q is 2;

R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O; and

R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl.

Embodiment 4

The compound according to any one of embodiments 1 to 3, wherein

one of R¹ and R² is —X—Y; or —W—R⁷—X—Y;

W is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

X is C₁-C₆ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;

Y is —C(O)OH; and

R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O.

Embodiment 5

The compound according to embodiment 1, wherein

one of R¹ and R² is —(CH₂)_(m)—C(O)OR″, or—(CH₂)_(m)—R⁷—(CH₂)_(n)—C(O)OR″;

m is 1, 2, 3, 4, 5, 6, 7 or 8;

n is 0, 1, 2 or 3;

R″ is H or C₁-C₄ alkyl optionally substituted by one or more halogenatoms; and

R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O.

Embodiment 6

The compound according to embodiments 5, wherein

one of R¹ and R² is —(CH₂)_(m)—C(O)OR″;

m is 3, 4, 5, 6, 7 or 8; and

R″ is H or C₁-C₄ alkyl optionally substituted by one or more halogenatoms.

Embodiment 7

The compound according to any one of embodiments 5 or 6, wherein

one of R¹ and R² is —(CH₂)_(m)—C(O)OR″;

R″ is H; and

m is 4, 5 or 6.

Embodiment 8

The compound according to embodiment 1, wherein

one of R¹ and R² is

Embodiment 9

The compound according to any one of embodiments 1 to 8, wherein

R² is H, C₁-C₈ alkyl optionally substituted by one or more halogenatoms, C₁-C₄ alkoxy, C₃-C₇cycloalkyl;

if present R^(2a) is H; or

R² and R^(2a) together are oxo;

R′ is H, C₁-C₄ alkyl.

Embodiment 10

The compound according to embodiment 9, wherein

R² is H, C₁-C₈ alkyl optionally substituted by one or more halogenatoms, C₁-C₄ alkoxy, C₃-C₇cycloalkyl.

Embodiment 11

The compound according to embodiment 10, wherein

R² is H, cyclopropyl, isopropyl, methoxy or methyl.

Embodiment 12

The compound according to any one of the preceding embodiments, wherein

R³ and R^(3a) are independently selected from H; C₁-C₄ alkyl optionallysubstituted by one or more halogen atoms or OH; —C(═O)H;—(C₀-C₄alkyl)-NR¹⁹R²¹ and OH; or R³ and R^(3a) taken together are oxo.

Embodiment 13

The compound according to any one of the preceding embodiments, wherein

R³ and R^(3a) are independently selected from H; C₁-C₄ alkyl optionallysubstituted by one or more halogen atoms or OH; —C(═O)H and OH; or R³and R^(3a) taken together are oxo.

Embodiment 14

The compound according to any one of the preceding embodiments, wherein

R⁵ and R⁶ are independently selected from C₆-C₁₄ aryl and 5 to 6membered heteroaryl, wherein the heteroaryl contains at least oneheteroatom selected from N, O and S, wherein the aryl and heteroaryl areeach optionally substituted by one or more Z substituents.

Embodiment 15

The compound according to any one of embodiments 1 to 13, wherein

R⁵ and R⁶ are independently selected from phenyl; 2-pyridyl, 3-pyridyl,or 4-pyridyl,

wherein the phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl are eachoptionally substituted by one or more Z substituents.

Embodiment 16

The compound according to any one of the embodiments 1 to 13, wherein

R⁵ and R⁶ are independently selected from phenyl optionally substitutedby OH, C₁-C₄ alkyl optionally substituted by one or more OH groups orNH₂ groups; C₁-C₄ alkyl optionally substituted by one or more halogenatoms; C₁-C₄ alkoxy optionally substituted by one or more OH groups orC₁-C₄ alkoxy; NR¹⁹R²¹; C(O)OR¹⁹; C(O)R¹⁹; SR¹⁹; OR¹⁹; CN; NO₂; andhalogen.

Embodiment 17

The compound according to any one of embodiments 1 to 13, wherein

R⁵ and R⁶ are independently selected from phenyl optionally substitutedby C₁-C₄ alkyl optionally substituted by one or more OH groups or NH₂groups; C₁-C₄ alkyl optionally substituted by one or more halogen atoms;C₁-C₄ alkoxy optionally substituted by one or more OH groups or C₁-C₄alkoxy; and halogen.

Embodiment 18

The compound according to any one of embodiments 1 to 13, wherein

R⁵ and R⁶ are independently selected from phenyl optionally substitutedby C₁-C₄ alkoxy or halogen, and C₁-C₄ alkyl optionally substituted byone or more halogen atoms.

Embodiment 19

The compound according to any one of embodiments 1 to 13, wherein

R⁵ and R⁶ are independently selected from phenyl optionally substitutedby methyl, ethyl, trifluoromethyl, methoxy or halogen.

Embodiment 20

The compound according to any one of embodiments 1 to 13, wherein

R⁵ is

and

R⁶ is

Embodiment 21

The compound according to any proceeding embodiment, wherein A is N.

Embodiment 22

The compound according to embodiment 1 to 21, wherein A is CR′.

Embodiment 23

The compound according to embodiment 22, wherein R′ is H.

Embodiment 24

The compound according to any one of embodiments 1 to 23, whereinformula Ib has the following stereochemistry:

Embodiment 25

The compound according to any one of embodiments 1 to 23, wherein thecompound is represented by formula (Ia)

or a pharmaceutically acceptable salt thereof.

Embodiment 26

The compound according to embodiment 1, wherein the compound isrepresented by formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein

A is N or CR;

R′ is H, C₁-C₈ alkyl optionally substituted by one or more halogenatoms;

R¹ is —X—Y; or R¹ is —W—R⁷—X—Y; or R¹ is —S(O)₂—X—Y; or R¹ is—S(O)₂—W—R⁷—X—Y;

R² is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; C₁-C₄ alkoxy; —(C₀-C₄ alkyl)-NR¹⁹R²¹ and C₃-C₇cycloalkyl;R³ is independently selected from H; C₁-C₈ alkyl optionally substitutedby one or more halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl orC₃-C₇ cycloalkyloxy; —OH; OR′; —(C₀-C₄alkyl)-NR¹⁹R²¹; CN; halogen;—(C₀-C₄alkyl)-C₆-C₁₄aryl; —(C₀-C₄alkyl)-4 to 14 membered heteroaryl;—C(═O)H; —C(═O)OH; —C(═O)NR¹⁹R²¹ and C₃-C₇ cycloalkyl, wherein the aryland heteroaryl are optionally substituted by one or more substituentsindependently selected from OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogens andC₁-C₄ haloalkyl;R⁵ and R⁶ are independently selected from —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and—(C₀-C₄ alkyl)-4 to 14 membered heteroaryl, wherein the aryl andheteroaryl are each optionally substituted by one or more Zsubstituents;W is C₁-C₈ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;X is C₁-C₈ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;Y is carboxy, C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or—CONH—S(O)_(q)—R^(x), wherein R^(x) is phenyl, benzyl or —NR¹⁹R²¹;q is 0, 1 or 2;R⁷ is a divalent moiety represented by —O—, —S—, —NHC(O)—, —CH₂═CH₂—,—C₆-C₁₄ aryl-D-; -3 to 14 membered heterocyclyl-D-, wherein theheterocyclyl contains at least one heteroatom selected from N, O and S,wherein D is O, S, NH or not present;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups, C₁-C₆ alkoxy optionallysubstituted by one or more halogen, C₁-C₆ alkoxy optionally substitutedby C₁-C₄ alkoxy, NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹, (SO₂)R²¹, NR¹⁸C(O)R²¹,C(O)NR¹⁹R²¹, NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹,SR¹⁹, OR¹⁹, oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclyl,wherein the heterocyclyl contains at least one heteroatom selected fromN, O and S;R¹⁸ is independently H or C₁-C₆ alkyl;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; —(C₁-C₄ alkyl)-carboxy; (C₀-C₄ alkyl)-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; (C₀-C₄ alkyl)-3- to 14-membered heterocyclyl,the heterocyclyl including one or more heteroatoms selected from N, Oand S, optionally substituted by one or more groups selected fromhalogen, oxo, C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-memberedheterocyclyl, the heterocyclyl including one or more heteroatomsselected from N, O and S, optionally substituted by one or more groupsselected from halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl;wherein the alkyl groups are optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C(O)NH₂, C(O)NHC₁-C₆ alkyl orC(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclyl, the heterocyclyl including one or morefurther heteroatoms selected from N, O and S, the heterocyclyl beingoptionally substituted by one or more substituents selected from OH;halogen; aryl; 5- to 10-membered heterocyclyl including one or moreheteroatoms selected from N, O and S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl;C₁-C₆ alkyl optionally substituted by one or more halogen atoms; C₁-C₆alkoxy optionally substituted by one or more OH groups or C₁-C₄ alkoxy;and C(O)OC₁-C₆ alkyl, wherein the aryl and heterocyclyl substituentgroups are themselves optionally substituted by C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ alkoxy.

Embodiment 27

The compound according to embodiment 1, wherein the compound isrepresented by formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein

A is N; R¹ is —X—Y; or R¹ is —S(O)₂—X—Y;

R² is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH or C₁-C₄ alkoxy; C₁-C₄ alkoxy; and C₃-C₇ cycloalkyl;R³ is independently selected from H; C₁-C₈ alkyl optionally substitutedby one or more halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl orC₃-C₇ cycloalkyloxy; —OH; —(C₀-C₄alkyl)-NR¹⁹R²¹; CN; halogen;—(C₀-C₄alkyl)-C₆-C₁₄aryl; —(C₀-C₄alkyl)-4 to 14 membered heteroaryl;—C(═O)H; —C(═O)OH; —C(═O)NR¹⁹R²¹ and C₃-C₇ cycloalkyl, wherein the aryland heteroaryl are optionally substituted by one or more substituentsindependently selected from OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogens andC₁-C₄ haloalkyl;R⁵ and R⁶ are independently selected from —(C₀-C₄ alkyl)-C₆-C₁₄ aryl and—(C₀-C₄ alkyl)-4 to 14 membered heteroaryl, wherein the aryl andheteroaryl are each optionally substituted by one or more Zsubstituents;X is C₁-C₈ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;Y is carboxy or C₁-C₄-alkoxycarbonyl;Z is independently OH, aryl, O-aryl, benzyl, O-benzyl, C₁-C₆ alkyloptionally substituted by one or more OH groups or NH₂ groups, C₁-C₆alkyl optionally substituted by one or more halogen atoms, C₁-C₆ alkoxyoptionally substituted by one or more OH groups, C₁-C₆ alkoxy optionallysubstituted by one or more halogen, C₁-C₆ alkoxy optionally substitutedby C₁-C₄ alkoxy, NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹, (SO₂)R²¹, C(O)NR¹⁹R²¹,NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹, NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹,oxo, CN, NO₂, halogen or a 3 to 14 membered heterocyclyl, wherein theheterocyclyl contains at least one heteroatom selected from N, O and S;R¹⁸ is independently H or C₁-C₆ alkyl;R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈ cycloalkyl;C₁-C₄ alkoxy-C₁-C₄ alkyl; —(C₁-C₄ alkyl)-carboxy; (C₀-C₄ alkyl)-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; (C₀-C₄ alkyl)-3- to 14-membered heterocyclyl,the heterocyclyl including one or more heteroatoms selected from N, Oand S, optionally substituted by one or more groups selected fromhalogen, oxo, C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄ alkyl)-O-aryloptionally substituted by one or more groups selected from C₁-C₆ alkyl,C₁-C₆ alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to 14-memberedheterocyclyl, the heterocyclyl including one or more heteroatomsselected from N, O and S, optionally substituted by one or more groupsselected from halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl;wherein the alkyl groups are optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C(O)NH₂, C(O)NHC₁-C₆ alkyl orC(O)N(C₁-C₆ alkyl)₂; orR¹⁹ and R²¹ together with the nitrogen atom to which they attached forma 5- to 10-membered heterocyclyl, the heterocyclyl including one or morefurther heteroatoms selected from N, O and S, the heterocyclyl beingoptionally substituted by one or more substituents selected from OH;halogen; aryl; 5- to 10-membered heterocyclyl including one or moreheteroatoms selected from N, O and S; S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl;C₁-C₆ alkyl optionally substituted by one or more halogen atoms; C₁-C₆alkoxy optionally substituted by one or more OH groups or C₁-C₄ alkoxy;and C(O)OC₁-C₆ alkyl, wherein the aryl and heterocyclyl substituentgroups are themselves optionally substituted by C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ alkoxy.

Embodiment 28

The compound according to embodiment 1, wherein the compound isrepresented by formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein

A is N; R¹ is —X—Y; or

R² is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH or C₁-C₄ alkoxy; C₁-C₄ alkoxy; and C₃-C₇ cycloalkyl;R³ is independently selected from H; C₁-C₈ alkyl optionally substitutedby one or more halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl orC₃-C₇ cycloalkyloxy; —OH; —(C₀-C₄alkyl)-NR¹⁹R²¹; CN; halogen;R⁵ and R⁶ are independently selected from —(C₀-C₄ alkyl)-phenyl, whereinthe phenyl is optionally substituted by one or more Z substituents;X is C₁-C₈ alkylene optionally substituted by hydroxy, halogens or C₁-C₄alkyl;Y is carboxy or C₁-C₄-alkoxycarbonyl;Z is independently OH, C₁-C₆ alkyl optionally substituted by one or moreOH groups or NH₂ groups, C₁-C₆ alkyl optionally substituted by one ormore halogen atoms, C₁-C₆ alkoxy optionally substituted by one or moreOH groups, C₁-C₆ alkoxy optionally substituted by one or more halogen,C₁-C₆ alkoxy optionally substituted by C₁-C₄ alkoxy.

Embodiment 29

The compound according to embodiment 1, wherein the compound isrepresented by formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein

A is N; R¹ is —X—Y; or

R² is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH or C₁-C₄ alkoxy; C₁-C₄ alkoxy; and C₃-C₇ cycloalkyl;R³ is independently selected from H; C₁-C₈ alkyl optionally substitutedby one or more halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl orC₃-C₇ cycloalkyloxy; —OH; —(C₀-C₄alkyl)-NR¹⁹R²¹; CN; halogen;X is C₄-C₇ alkylene;Y is carboxy or C₁-C₄-alkoxycarbonyl.

Embodiment 30

The compound according to embodiment 1, the compound is selected from

-   7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   ethyl    7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(6-isopropyl-2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid;-   ethyl    7-(6-isopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl    ester;-   7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid;-   7-(7-formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   ethyl    7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   ethyl    7-(7-((isopropylamino)methyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(7-((isopropylamino)methyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-methoxy-2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid;-   ethyl    7-(2,3-di-p-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   5-(2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)-pentanoic acid;-   2-(5-(2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)acetic    acid;-   7-(6-methyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid;-   7-(6-cyclopropyl-2-(4-methoxy-phenyl)-3-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(2,3-bis(4-chlorophenyl)-6-cyclopropyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2-(4-ethylphenyl)-3-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2,3-di-m-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(4-ethylphenyl)-2-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(4-methoxyphenyl)-2-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(m-tolyl)-2-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2-(m-tolyl)-3-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-(2-Hydroxyethyl)-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   5-(6-Cyclopropyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)pentanoic    acid;-   6-(6-Cyclopropyl-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)hexanoic    acid;-   7-(7-(Methoxymethyl)-2,3-dip-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-oxo-2,3-dip-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(2,3-Dip-tolyl-6-(trifluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid; and-   7-(6,7-Diethyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;    or a pharmaceutically acceptable salt thereof.

Embodiment 31

The compound according to embodiment 1, the compound is

-   7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   ethyl    7-(6-cyclopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(6-isopropyl-2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid;-   ethyl    7-(6-isopropyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl    ester;-   7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid;-   7-(7-formyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   ethyl    7-(7-(hydroxymethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   ethyl    7-(7-((isopropylamino)methyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   7-(7-((isopropylamino)methyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-methoxy-2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid;-   ethyl    7-(2,3-di-p-tolyl-6,7-dihydro-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate;-   5-(2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)-pentanoic acid;-   2-(5-(2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)pentanamido)acetic    acid;-   7-(6-methyl-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2,3-diphenyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic    acid;-   7-(6-cyclopropyl-2-(4-methoxy-phenyl)-3-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(2,3-bis(4-chlorophenyl)-6-cyclopropyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2-(4-ethylphenyl)-3-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-2,3-di-m-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(4-ethylphenyl)-2-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(4-methoxyphenyl)-2-(p-tolyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoic    acid;-   7-(6-cyclopropyl-3-(m-tolyl)-2-(p-tolyl)-5H-pyrrolo[2,    3-1)]pyrazin-5-yl)heptanoic acid;-   7-(6-cyclopropyl-2-(m-tolyl)-3-(p-tolyl)-5H-pyrrolo[2,    3-1)]pyrazin-5-yl)heptanoic acid;    or a pharmaceutically acceptable salt thereof.

Embodiment 32

The compound according to any one of embodiments 1 to 31, or apharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 33

The compound according to any one of embodiments 1 to 31, or apharmaceutically acceptable salt thereof, for use in the treatment of adisorder or disease mediated by the IP receptor.

Embodiment 34

The compound according to any one of embodiments 1 to 31, or apharmaceutically acceptable salt thereof, for use in the treatment of adisorder or disease selected from PAH, disorders in need of antiplatelettherapy, atherosclerosis, asthma, COPD, hyperglycemia, inflammatorydisease and fibrotic diseases.

Embodiment 35

The compound according to any one of embodiments 1 to 31, or apharmaceutically acceptable salt thereof, for use in the treatment of adisorder or disease selected from PAH, atherosclerosis, asthma, COPD,hyperglycemia and fibrotic diseases.

Embodiment 36

The compound according to any one of embodiments 1 to 31, or apharmaceutically acceptable salt thereof, for use in the treatment of adisorder or disease selected from PAH, asthma, COPD and cystic fibrosis.

Embodiment 37

The compound according to any one of embodiments 1 to 31, or apharmaceutically acceptable salt thereof, for use in the treatment of adisorder or disease selected from PAH or COPD.

Embodiment 38

The compound according to any one of embodiments 1 to 31, or apharmaceutically acceptable salt thereof, for use in the treatment ofPAH.

Embodiment 39

A pharmaceutical composition, comprising:

a therapeutically effective amount of the compound according to any oneof claims 1 to 31, or a pharmaceutically acceptable salt thereof, andone or more pharmaceutically acceptable carriers.

Embodiment 40

A pharmaceutical combination, comprising:

a therapeutically effective amount of the compound according to any oneof claims 1 to 31, or a pharmaceutically acceptable salt thereof, anda second active agent.

Embodiment 41

Use of a compound according to any one of claims 1 to 26, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disorder or disease mediated by the IPreceptor.

Embodiment 42

Use of a compound according to any one of claims 1 to 31, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disorder or disease selected from PAH,atherosclerosis, asthma, COPD, hyperglycemia and fibrotic diseases.

Embodiment 43

Use of a compound according to any one of claims 1 to 31, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disorder or disease selected from PAH,asthma, COPD and cystic fibrosis.

Embodiment 44

Use of a compound according to any one of claims 1 to 31, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a disorder or disease selected from PAHor COPD.

Embodiment 45

Use of a compound according to any one of claims 1 to 31, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of PAH.

Embodiment 46

Use of a compound according to any one of claims 1 to 31, or apharmaceutically acceptable salt thereof, for the treatment of pulmonaryarterial hypertension.

Embodiment 47

A method for the prevention or treatment of a condition affected byactivation of the IP receptor, comprising:

administering an effective amount to activate the IP receptor of atleast one compound according to any of claims 1 to 31 to a subject inneed of such treatment.

Embodiment 48

A method of treating a disorder or disease selected from PAH, disordersin need of antiplatelet therapy, atherosclerosis, asthma, COPD,hyperglycemia, inflammatory disease and fibrotic diseases in a patientin need thereof, comprising:

administering to the subject in need thereof a therapeutically effectiveamount of the compound according to any one of claims 1 to 31, or apharmaceutically acceptable salt thereof.

We claim:
 1. A compound represented by formula

or a pharmaceutically acceptable salt thereof, wherein A is N or CR; R′is H, C₁-C₈ alkyl optionally substituted by one or more halogen atoms;R¹ is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; —(C₂-C₄ alkyl)-NR¹⁹R²¹ and C₃-C₇ cycloalkyl; or R¹ is—X—Y; or R¹ is —W—R⁷—X—Y; or R¹ is —S(O)₂—X—Y; or R¹ is —S(O)₂—W—R⁷—X—Y;R² is selected from H; C₁-C₈ alkyl optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇cycloalkyloxy; C₁-C₄ alkoxy; —(C₀-C₄ alkyl)-NR¹⁹R²¹ and C₃-C₇cycloalkyl; or R² is —X—Y; or R² is —W—R⁷—X—Y; or R² is —S(O)₂—X—Y; orR² is —S(O)₂—W—R⁷—X—Y; R^(2a) is selected from H; C₁-C₈ alkyl optionallysubstituted by one or more halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇cycloalkyl or C₃-C₇ cycloalkyloxy; and C₃-C₇ cycloalkyl; or R² andR^(2a) taken together are oxo; wherein one of R¹ and R² is —X—Y,—W—R⁷—X—Y, —S(O)₂—X—Y; or —S(O)₂—W—R⁷—X—Y; R³ is independently selectedfrom H; C₁-C₈ alkyl optionally substituted by one or more halogen atoms,OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl or C₃-C₇ cycloalkyloxy; —OH; OR′;—(C₀-C₄alkyl)-NR¹⁹R²¹; CN; halogen; —(C₀-C₄alkyl)-C₆-C₁₄aryl;—(C₀-C₄alkyl)-4 to 14 membered heteroaryl; —C(═O)H; —C(═O)OH;—C(═O)NR¹⁹R²¹ and C₃-C₇ cycloalkyl, wherein the aryl and heteroaryl areoptionally substituted by one or more substituents independentlyselected from OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, halogens and C₁-C₄haloalkyl; R^(3a) is selected from H; C₁-C₈ alkyl optionally substitutedby one or more halogen atoms, OH, C₁-C₄ alkoxy, C₃-C₇ cycloalkyl orC₃-C₇ cycloalkyloxy; and C₃-C₇ cycloalkyl; or R³ and R^(3a) takentogether are oxo; R⁵ and R⁶ are independently selected from —(C₀-C₄alkyl)-C₆-C₁₄ aryl and —(C₀-C₄ alkyl)-4 to 14 membered heteroaryl,wherein the aryl and heteroaryl are each optionally substituted by oneor more Z substituents; W is C₁-C₈ alkylene optionally substituted byhydroxy, halogens or C₁-C₄ alkyl; X is C₁-C₈ alkylene optionallysubstituted by hydroxy, halogens or C₁-C₄ alkyl; Y is carboxy,C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or —CONH—S(O)_(q)—R^(x),wherein R^(x) is phenyl, benzyl or —NR¹⁹R²¹; q is 0, 1 or 2; R⁷ is adivalent moiety represented by —O—, —S—, —NHC(O)—, —CH₂═CH₂—, —C₆-C₁₄aryl-D-; -3 to 14 membered heterocyclyl-D-, wherein the heterocyclylcontains at least one heteroatom selected from N, O and S, wherein D isO, S, NH or not present; Z is independently OH, aryl, O-aryl, benzyl,O-benzyl, C₁-C₆ alkyl optionally substituted by one or more OH groups orNH₂ groups, C₁-C₆ alkyl optionally substituted by one or more halogenatoms, C₁-C₆ alkoxy optionally substituted by one or more OH groups,C₁-C₆ alkoxy optionally substituted by one or more halogen, C₁-C₆ alkoxyoptionally substituted by C₁-C₄ alkoxy, NR¹⁸(SO₂)R²¹, (SO₂)NR¹⁹R²¹,(SO₂)R²¹, NR¹⁸C(O)R²¹, C(O)NR¹⁹R²¹, NR¹⁸C(O)NR¹⁹R²¹, NR¹⁸C(O)OR¹⁹,NR¹⁹R²¹, C(O)OR¹⁹, C(O)R¹⁹, SR¹⁹, OR¹⁹, oxo, CN, NO₂, halogen or a 3 to14 membered heterocyclyl, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S; R¹⁸ is independently H or C₁-C₆alkyl; R¹⁹ and R²¹ are each independently H; C₁-C₈ alkyl; C₃-C₈cycloalkyl; C₁-C₄ alkoxy-C₁-C₄ alkyl; —(C₁-C₄ alkyl)-carboxy; (C₀-C₄alkyl)-aryl optionally substituted by one or more groups selected fromC₁-C₆ alkyl, C₁-C₆ alkoxy and halogen; (C₀-C₄ alkyl)-3- to 14-memberedheterocyclyl, the heterocyclyl including one or more heteroatomsselected from N, O and S, optionally substituted by one or more groupsselected from halogen, oxo, C₁-C₆ alkyl and C(O)C₁-C₆ alkyl; (C₀-C₄alkyl)-O-aryl optionally substituted by one or more groups selected fromC₁-C₆ alkyl, C₁-C₆ alkoxy and halogen; and (C₀-C₄ alkyl)-O-3- to14-membered heterocyclyl, the heterocyclyl including one or moreheteroatoms selected from N, O and S, optionally substituted by one ormore groups selected from halogen, C₁-C₆ alkyl or C(O)C₁-C₆ alkyl;wherein the alkyl groups are optionally substituted by one or morehalogen atoms, OH, C₁-C₄ alkoxy, C(O)NH₂, C(O)NHC₁-C₆ alkyl orC(O)N(C₁-C₆ alkyl)₂; or R¹⁹ and R²¹ together with the nitrogen atom towhich they attached form a 5- to 10-membered heterocyclyl, theheterocyclyl including one or more further heteroatoms selected from N,O and S, the heterocyclyl being optionally substituted by one or moresubstituents selected from OH; halogen; aryl; 5- to 10-memberedheterocyclyl including one or more heteroatoms selected from N, O and S;S(O)₂-aryl; S(O)₂—C₁-C₆ alkyl; C₁-C₆ alkyl optionally substituted by oneor more halogen atoms; C₁-C₆ alkoxy optionally substituted by one ormore OH groups or C₁-C₄ alkoxy; and C(O)OC₁-C₆ alkyl, wherein the aryland heterocyclyl substituent groups are themselves optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxy.
 2. Thecompound according to claim 1, wherein wherein one of R¹ and R² is —X—Y,—W—R⁷—X—Y, —S(O)₂—X—Y; or —S(O)₂—W—R⁷—X—Y; W is C₁-C₆ alkyleneoptionally substituted by hydroxy, halogens or C₁-C₄ alkyl; X is C₁-C₆alkylene optionally substituted by hydroxy, halogens or C₁-C₄ alkyl; Yis carboxy, C₁-C₄-alkoxycarbonyl, tetrazolyl, —C(═O)NR¹⁹R²¹ or—CONH—S(O)_(q)—R^(x), wherein R^(x) is phenyl, benzyl or —NR¹⁹R²¹; q is2; R⁷ is a divalent moiety represented by —C₆-C₁₄ aryl-D-; -3 to 14membered heterocyclyl-D-, wherein the heterocyclyl contains at least oneheteroatom selected from N, O and S, wherein D is O; and R¹⁹ and R²¹ areeach independently H; C₁-C₈ alkyl.
 3. The compound according to claim 1,wherein one of R¹ and R² is —(CH₂)_(m)—C(O)OR″; m is 3, 4, 5, 6, 7 or 8;and R″ is H or C₁-C₄ alkyl optionally substituted by one or more halogenatoms.
 4. The compound according to claim 1, wherein R² is H, C₁-C₈alkyl optionally substituted by one or more halogen atoms, C₁-C₄ alkoxy,OH, or OR′; if present R^(2a) is H; or R² and R^(2a) together are oxo;R′ is H, C₁-C₈ alkyl.
 5. The compound according to claim 1, wherein R⁵and R⁶ are independently selected from C₆-C₁₄ aryl and 5 to 6 memberedheteroaryl, wherein the heteroaryl contains at least one heteroatomselected from N, O and S, wherein the aryl and heteroaryl are eachoptionally substituted by one or more Z substituents.
 6. The compoundaccording to claim 5, wherein R⁵ and R⁶ are independently selected fromphenyl optionally substituted by OH, C₁-C₄ alkyl optionally substitutedby one or more OH groups or NH₂ groups; C₁-C₄ alkyl optionallysubstituted by one or more halogen atoms; C₁-C₄ alkoxy optionallysubstituted by one or more OH groups or C₁-C₄ alkoxy; NR¹⁹R²¹; C(O)OR¹⁹;C(O)R¹⁹; SR¹⁹; OR¹⁹; CN; NO₂; and halogen.
 7. The compound according toclaim 1, wherein A is N.
 8. A pharmaceutical composition, comprising: atherapeutically effective amount of the compound according to claim 1,or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers.
 9. A pharmaceutical combination,comprising: a therapeutically effective amount of the compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, and a secondactive agent.
 10. A method for the prevention or treatment of a disorderor disease selected from PAH, disorders in need of antiplatelet therapy,atherosclerosis, asthma, COPD, hyperglycemia, inflammatory disease andfibrotic disease, comprising: administering an effective amount of atleast one compound according to claim 1 to a subject in need of suchtreatment.
 11. The method according to claim 10, wherein the disease isselected from PAH, asthma, COPD and fibrotic disease.
 12. The methodaccording to claim 10, wherein the diseases is selected from PAH,asthma, COPD and cystic fibrosis.
 13. The method according to claim 10,wherein the disease is selected from PAH and COPD.
 14. The methodaccording to claim 10, wherein the disease is PAH.